Dietary Adequacy Among Young Children in India: Improvement or Stagnation? An Investigation From the National Family Health Survey.
This study assessed the trend of minimum acceptable dietary practices among children aged 6 to 23 months in India in the past decade. Data collected in the National Family Health Survey during 2005 to 2006 (NFHS-3) and 2015 to 2016 (NFHS-4) were used. The sample size for this study was 11 727 children for NFHS-3 and 61 158 children for NFHS-4. Bivariate and multivariate analyses were done to identify the predictors of feeding practices. We analyzed data of last-born singleton children aged 6 to 23 months who were living with their mother (ever-married women aged 15-49 years). In India, a low proportion (10%) of children aged 6 to 23 months received a minimum acceptable diet, and its estimate remained the same in the past 10 years. Older mothers, educated mothers, antenatal care, high economic status, and place of residence were the most consistent predictors of minimum acceptable dietary intake. Over the past decade, however, the minimum acceptable dietary intake has declined among older children (odds ratio [OR] = 0.57, 95% confidence interval [CI], 0.47-0.70; P < .001), children with overweight mothers (OR = 0.40, 95% CI, 0.31-0·50; P <.001), and children of well-off families (OR = 0.29, 95% CI, 0.23-0.37; P < .001). The odds for minimum acceptable dietary intake were significantly higher among children of high (4+) birth order (OR = 1.74, 95% CI, 1.41-2.15; P < .001), rural areas, and children living in the central, eastern, and north-eastern region. Results indicate the need for further investigations of poor dietary intake among children living in well-off families and in the northern region. This study suggests policymakers and program managers to address contextual barriers against minimum acceptable dietary intake among children and to reconsider existing strategies in India.


Ultrasensitive serum interferon-α quantification during SLE remission identifies patients at risk for relapse.
Maintenance of remission has become central in the management of systemic lupus erythematosus (SLE). The importance of interferon-alpha (IFN-α) in the pathogenesis of SLE notwithstanding, its expression in remission has been poorly studied as yet. To study its expression in remission and its prognostic value in the prediction of a disease relapse, serum IFN-α levels were determined using an ultrasensitive single-molecule array digital immunoassay which enables the measurement of cytokines at physiological concentrations. A total of 254 SLE patients in remission, according to the Definition of Remission in SLE classification, were included in the study. Serum IFN-α concentrations were determined at baseline and patients were followed up for 1 year. Lupus flares were defined according to the Safety of Estrogens in Lupus Erythematosus: National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index Flare Index, whereas the Kaplan-Meier analysis and Cox regression analysis were used to estimate the time to relapse and to identify baseline factors associated with time to relapse, respectively. Of all patients in remission, 26% displayed abnormally high IFN-α serum levels that were associated with the presence of antibodies specific for ribonucleoprotein (RNP), double stranded (ds)DNA and Ro/SSA60, as well as young age. Importantly, elevated-baseline IFN-α serum levels and remission duration were associated in an independent fashion, with shorter time to relapse, while low serum levels of complement component 3 and anti-dsDNA Abs were not. Direct serum IFN-α assessment with highly sensitive digital immunoassay permits clinicians to identify a subgroup of SLE patients, clinically in remission, but at higher risk of relapse.


Photodynamic therapy involves an antiangiogenic mechanism and is enhanced by ferrochelatase inhibitor in urothelial carcinoma.
The purpose of the present study was to investigate the mechanism of photodynamic therapy (PDT) supplemented with exogenously added 5-aminolevulinic acid (ALA) on human urothelial cancer (UC). Moreover, we aimed to determine whether the therapeutic effects of ALA-based PDT (ALA-PDT) for UC could be enhanced by deferoxamine (DFX), an inhibitor of ferrochelatase. The efficiency of ALA-PDT on these cells was analyzed using flow cytometry and the type of cell death was also assessed. The ALA-PDT promoting effect of DFX was examined on both UC cells and human umbilical vein endothelial cells (HUVEC). The ALA-PDT decreased levels of mitochondrial membrane potential and induced cell death mainly via apoptosis in these cells. Moreover, inhibition of ferrochelatase by DFX led to an increase of protoporphyrin IX (PpIX) accumulation and enhanced the effect of ALA-PDT on UC cells. We further investigated the effect of DFX on in vivo PDT with a tumor-bearing animal model and found that DFX efficiently enhanced tumor cell apoptosis. ALA-PDT induced death of neovascular endothelial cells in tumors but did not affect small vessel endothelial cells in normal tissues surrounding the tumor. Furthermore, DFX enhanced inhibition of neovascularization. These results demonstrated ALA-PDT dominantly induced apoptosis over necrosis by direct action on UC as well as via antiangiogenic action on neovacular endothelial cells, suggesting that the therapeutic damage by ALA-PDT could be kept to a minimum in the surrounding normal tissues. In addition, increased accumulation of PpIX by DFX could enhance this effectiveness of ALA-PDT.


Immunohematopoietic stem cell transplantation: introduction and 35 years of development in South Africa--the historical and scientific perspective.
Bone marrow was the traditional graft source when we introduced these procedures to South Africa. Technical details were established using rabbits as the experimental model with translation into a formally structured clinical programme at the University of Cape Town, based in the Groote Schuur Hospital, in 1972. Lack of any infrastructure was overcome by the acquisition of the first continuous-flow cell separator in sub-Sahara to provide for granulocyte transfusions. This was shortly followed by creating a dedicated platelet donor panel and establishing a specialized laboratory for clonogenic assays, flow cytometry, and programmed freezing and by including cryopreservation. Development was constant and seamless but four distinct periods are recognizable. First, guided and constantly encouraged by Professor E Donnall Thomas, was the use of an unfractionated mononuclear population derived from multiple sternal and iliac crest aspirations where complications, as in other centres, included rejection and, particularly troublesome, acute as well as chronic GVHD. The second was centred on CsA in association with Professor Jean Borel at Sandoz in Basle, leading to a decrease in the incidence and severity of the latter immunologic phenomena but not to their abrogation. Third was the opportunity of working with Professor Herman Waldmann and Dr Geoff Hale, first in Cambridge and latterly in Oxford, on immunosuppression achieved by ex vivo T-cell depletion within the broad ambit of the Campath users group. It was here that there was pioneered the alternative new approach of adding the anti-CD 52 MoAb only to the graft in what has become known as the in-the-bag technique. The fourth, securely based on early laboratory and clinical experiences, was a switch to the use of PBSCs mobilized into the circulation with stimulatory peptides. In 1995, this original transplant team relocated to a new academic centre in the private sector and has continued to actively refine the programme over the subsequent decade: the facility at Groote Schuur hospital continues independently. Early recognition that accountability for these expensive and high profile procedures was an important obligation led to consecutive transplants being reported to the International and Autologous registries and now continuing to the Centre for Bone Marrow Transplant Research concurrently with the European Bone Marrow Transplant Registry. This disciplined approach has ensured that all data undergo constant audit and, on such a basis, underpin the unbroken accreditation extending over more than three and a half decades. With difficulties in finding sibling donors, a further achievement was the creation of The South African Bone Marrow Registry and now a proposal to also start a national transplant registry that will complement the survey currently being conducted, on a worldwide basis, by the European Group for Blood and Marrow Transplantation. It is concluded that a properly constituted and functioning multidisciplinary team can cost-effectively carry out immunohematopoietic stem cell grafting even in an under-resourced country with an outcome approximating that reported from recognized First World reference centres. The caveat is that, outside such comprehensive units, results may be less impressive, thereby arguing for resource allocation being directed to academically designated, rather than incentive-driven, preferred providers.


Development and external validation of multivariable risk models to predict incident and resolved neuropathic pain: a DOLORisk Dundee study.
Neuropathic pain is difficult to treat, and an understanding of the risk factors for its onset and resolution is warranted. This study aimed to develop and externally validate two clinical risk models to predict onset and resolution of chronic neuropathic pain. Participants of Generation Scotland: Scottish Family Health Study (GS; general Scottish population; n = 20,221) and Genetic of Diabetes Audit and Research in Tayside Scotland (GoDARTS; n = 5236) were sent a questionnaire on neuropathic pain and followed- -up 18 months later. Chronic neuropathic pain was defined using DN4 scores (≥ 3/7) and pain for 3 months or more. The models were developed in GS using logistic regression with backward elimination based on the Akaike information criterion. External validation was conducted in GoDARTS and assessed model discrimination (ROC and Precision-Recall curves), calibration and clinical utility (decision curve analysis [DCA]). Analysis revealed incidences of neuropathic pain onset (6.0% in GS [236/3903] and 10.7% in GoDARTS [61/571]) and resolution (42.6% in GS [230/540] and 23.7% in GoDARTS [56/236]). Psychosocial and lifestyle factors were included in both onset and resolved prediction models. In GoDARTS, these models showed adequate discrimination (ROC = 0.636 and 0.699), but there was evidence of miscalibration (Intercept = - 0.511 and - 0.424; slope = 0.623 and 0.999). The DCA indicated that the models would provide clinical benefit over a range of possible risk thresholds. To our knowledge, these are the first externally validated risk models for neuropathic pain. The findings are of interest to patients and clinicians in the community, who may take preventative or remedial measures.


Changes in the activation and function of the ankle plantar flexor muscles due to gait retraining in chronic stroke survivors.
A common goal of persons post-stroke is to regain community ambulation. The plantar flexor muscles play an important role in propulsion generation and swing initiation as previous musculoskeletal simulations have shown. The purpose of this study was to demonstrate that simulation results quantifying changes in plantar flexor activation and function in individuals post-stroke were consistent with (1) the purpose of an intervention designed to enhance plantar flexor function and (2) expected muscle function during gait based on previous literature. Three-dimensional, forward dynamic simulations were created to determine the changes in model activation and function of the paretic ankle plantar flexor muscles for eight patients post-stroke after a 12-weeks FastFES gait retraining program. An median increase of 0.07 (Range [-0.01,0.22]) was seen in simulated activation averaged across all plantar flexors during the double support phase of gait from pre- to post-intervention. A concurrent increase in walking speed and plantar flexor induced forward center of mass acceleration by the plantar flexors was seen post-intervention for seven of the eight subject simulations. Additionally, post-training, the plantar flexors had an simulated increase in contribution to knee flexion acceleration during double support. For the first time, muscle-actuated musculoskeletal models were used to simulate the effect of a gait retraining intervention on post-stroke muscle model predicted activation and function. The simulations showed a new pattern of simulated activation for the plantar flexor muscles after training, suggesting that the subjects activated these muscles with more appropriate timing following the intervention. Functionally, simulations calculated that the plantar flexors provided greater contribution to knee flexion acceleration after training, which is important for increasing swing phase knee flexion and foot clearance.


Drug therapy for symptoms associated with anxiety in adult palliative care patients.
This is an update of the review published on 'Drug therapy for anxiety in adult palliative care patients' in Issue 1, 2004 of The Cochrane Library. Anxiety is common in palliative care patients. It can be a natural response to impending death, but it may represent a clinically significant issue in its own right. It may also result from pain, or other untreated or poorly managed symptoms. When anxiety is severe or distressing drug therapy may be considered in addition to supportive care. This review aimed to identify and evaluate randomised controlled trials examining the effectiveness of drug therapy for symptoms of anxiety in adult palliative care patients. We searched the following sources: CENTRAL (The Cochrane Library 2012, Issue 2), MEDLINE (1966 to 2012), EMBASE (1980 to 2012), CINAHL (1982 to 2012), PsycLit (1974 to 2000) and PsycInfo (1990 to 2012) for literature pertaining to this topic published in any language using a detailed search strategy. We sought prospective, randomised trials, with or without blinding, involving the use of drug therapy for the treatment of symptoms of anxiety in adult palliative care patients. Pharmacological agents included 5-HT3 receptor antagonists, anxiolytic agents, antiepileptic agents, antidepressive agents, antipsychotic agents, benzodiazepines, butyrophenones, phenothiazines, antihistamines, barbiturates, sedative hypnotics, antiepileptic drugs and beta-blockers. We identified and excluded six studies using the original search strategy, with a further two studies being identified and excluded for this 2012 update. We therefore identified a total of eight potential studies but none met the criteria for inclusion in this review. No data were available to enable an assessment to be made of the effectiveness of drugs to treat symptoms of anxiety in palliative care patients. There remains insufficient evidence to draw a conclusion about the effectiveness of drug therapy for symptoms of anxiety in adult palliative care patients. To date no studies have been found that meet the inclusion criteria for this review. Prospective controlled clinical trials are required in order to establish the benefits and harms of drug therapy for the treatment of anxiety in palliative care.


Cryopreservation of Potato Shoot Tips for Long-Term Storage.
Cryopreservation is currently the only method which allows long-term conservation of living clonal plant material in the vapor or liquid phase of nitrogen (at -140 to -196 °C) allowing tissue to be viable for decades or perhaps centuries. Specifically, for species with recalcitrant seeds or requiring constant vegetative propagation, it is the method of choice for the long-term conservation of its genetic resources. The protocol described here is a modification of a previously developed plant vitrification solution 2 (PVS2)-droplet vitrification method of potato shoot tips, adapted from Musa species. Utilizing this protocol, the International Potato Center (CIP) has successfully stored in the cryobank more than 3000 cultivated potato accessions, belonging to seven species and nine different taxa [16], originating principally from ten countries in South and Central America. As part of CIP's quality management system, all vegetative material placed in cryo is routinely subsampled, thawed, and assessed to confirm that whole plantlets can be produced after storage in liquid nitrogen. Complete plant recovery rates of thawed shoot tips range from 20% to 100% (average rate: 60%). This chapter describes the complete set of steps from the routine procedure of cryopreserving potato shoot tips for long-term conservation.


Security interventions for workplace violence in the emergency department.
Despite a policy of zero tolerance towards workplace violence (WPV) in Australian public hospital EDs, the incidence of WPV continues to increase. The aim of this study was to characterise security responses to WPV within an adult level 4 ED. A retrospective single-centre review of episodes of WPV perpetrated by adults occurring within the ED was conducted between 1 January 2013 and 31 December 2015. Cases were identified using a prospectively recorded security register that records all events of security personnel attendance. The presence of police officers on initial presentation was the primary exposure variable. There were 1853 violent episodes committed by 1224 patients requiring security intervention during the study period, with half the episodes (n = 916; 49%) involving perpetrators who had committed at least two or more violent acts during the study period. Most cases (n = 1057, 57%; 95% CI: 55-59) occurred in the absence of police presence. Only 144 (7.8%) cases were managed by the presence of security personnel without physical security interventions. EDs should not rely on police response to prevent or handle violence. The finding of a high proportion of events being perpetrated by repeat offenders indicate that data sharing between EDs for identification of perpetrators of WPV can be useful for prevention of future episodes. ACEM policy for WPV in EDs should encompass further details on security credentialing and preventive strategies towards minimisation of WPV in the Australian EDs.


Adult cancer risk in women who were breastfed as infants: large UK prospective study.
There are known short-term benefits in breastfed infants versus bottle-fed infants in terms of lower risks of infection and obesity in infancy and childhood, but the long-term effect on the risk of adult cancers is unclear. In a cohort of 1 in 4 UK women born in 1935-1950 we report the incidence of adult cancers in relation to having been breastfed in infancy. In median year 2001 (interquartile range 2000-2003) 548,741 women without prior cancer reported whether they had been breastfed. There was 81% agreement between women's report of having been breastfed and information on breastfeeding recorded when they were 2 years old. Participants were followed by record-linkage to national cancer registration, hospital admission and death databases. Cox regression yielded adjusted relative risks (RRs) and 95% confidence intervals (CI) by having been breastfed or not for eight cancer sites with > 2000 incident cases and for related conditions, where appropriate. Of the eight cancers examined here one association was highly statistically significant: an increase in colorectal cancer incidence among women who had been breastfed versus not (RR 1.18, 95% CI 1.12-1.24, n = 8651). To investigate further the findings for colorectal cancer, we studied eight other gastro-intestinal conditions, and found increased risks in women who had been breastfed versus not for benign colorectal polyps (RR 1.09, 95% CI 1.05-1.13, n = 17,677) and for appendicitis (RR 1.19, 95% CI 1.07-1.31, n = 2108). The greater risks of adult colorectal cancer, colorectal polyps and appendicitis associated with having been breastfed in infancy suggest possible long-term effects of infant feeding practices on the gastrointestinal tract. Further studies are required to clarify this novel association.


Neonatal Acute Kidney Injury.
In recent years, there have been significant advancements in our understanding of acute kidney injury (AKI) and its impact on outcomes across medicine. Research based on single-center cohorts suggests that neonatal AKI is very common and associated with poor outcomes. In this state-of-the-art review on neonatal AKI, we highlight the unique aspects of neonatal renal physiology, definition, risk factors, epidemiology, outcomes, evaluation, and management of AKI in neonates. The changes in renal function with gestational and chronologic age are described. We put forth and describe the neonatal modified Kidney Diseases: Improving Global Outcomes AKI criteria and provide the rationale for its use as the standardized definition of neonatal AKI. We discuss risk factors for neonatal AKI and suggest which patient populations may warrant closer surveillance, including neonates <1500 g, infants who experience perinatal asphyxia, near term/ term infants with low Apgar scores, those treated with extracorporeal membrane oxygenation, and those requiring cardiac surgery. We provide recommendations for the evaluation and treatment of these patients, including medications and renal replacement therapies. We discuss the need for long-term follow-up of neonates with AKI to identify those children who will go on to develop chronic kidney disease. This review highlights the deficits in our understanding of neonatal AKI that require further investigation. In an effort to begin to address these needs, the Neonatal Kidney Collaborative was formed in 2014 with the goal of better understanding neonatal AKI, beginning to answer critical questions, and improving outcomes in these vulnerable populations.


Identification of kinship and occupant status in Mongolian noble burials of the Yuan Dynasty through a multidisciplinary approach.
The Yuan Dynasty (AD 1271-1368) was the first dynasty in Chinese history where a minority ethnic group (Mongols) ruled. Few cemeteries containing Mongolian nobles have been found owing to their tradition of keeping burial grounds secret and their lack of historical records. Archaeological excavations at the Shuzhuanglou site in the Hebei province of China led to the discovery of 13 skeletons in six separate tombs. The style of the artefacts and burials indicate the cemetery occupants were Mongol nobles. However, the origin, relationships and status of the chief occupant (M1m) are unclear. To shed light on the identity of the principal occupant and resolve the kin relationships between individuals, a multidisciplinary approach was adopted, combining archaeological information, stable isotope data and molecular genetic data. Analysis of autosomal, mitochondrial and Y-chromosomal DNA show that some of the occupants were related. The available evidence strongly suggests that the principal occupant may have been the Mongol noble Korguz. Our study demonstrates the power of a multidisciplinary approach in elucidating information about the inhabitants of ancient historical sites.


Genetic evidence for transcriptional activation by the yeast IME1 gene product.
IME1 is required in yeast for meiosis and for expression of IME2 and other early meiotic genes. IME1 is a 360-amino acid polypeptide with central and C-terminal tyrosine-rich regions. We report here that a fusion protein composed of the lexA DNA-binding domain and IME1 activates transcription in vivo of a reporter gene containing upstream lexA binding sites. Activation by the fusion protein shares several features with natural IME1 activity: both are dependent on the RIM11 gene product; both are impaired by the same ime1 missense mutations; both are restored by intragenic suppressors. The central tyrosine-rich region is sufficient to activate transcription when fused to lexA. Deletion of this putative activation domain results in a defective IME1 derivative. Function of the deletion derivative is restored by fusion to the acidic Herpesvirus VP16 activation domain. The C-terminal tyrosine-rich region is dispensable for transcriptional activation; rather it renders activation dependent upon starvation and RIM11. Immunofluorescence studies indicate that an IME1-lacZ fusion protein is concentrated in the nucleus. These observations are consistent with a model in which IME1 normally stimulates IME2 expression by providing a transcriptional activation domain at the IME2 5' regulatory region.


Exploring the Influence of Mutation on Transthyretin Aggregation in Heart Disease.
Transthyretin (TTR) is the transporter protein (55 kDa) that carries retinolbinding protein and Thyroxin (T4) in its functional tetramer form. Presence of the mutation in this protein (TTR) may lead to the dissociation of tetramers to monomer which unfolds and self-associates to form amyloid aggregates. Aggregation of this protein has been found to be associated with various lifethreatening disorders such as Coronary Artery Disease (CAD) which is the major cause of mortality and morbidity worldwide. In the present communication, we have predicted mutation prone residues of TTR with the help of suspect server. Substitution (T139R with 95 score) occurring at the thyroid hormone binding site was selected for studying the mutational consequences on TTR. The effect of mutation on stability, functionality, aggregation and folding rate was analyzed by MuPro, DUET, SDM, SNAP2, Polyphen2, PASTA2.0, Aggrescan and Folding RaCe servers. The presence of TTR monomer in CAD plasma has been observed through Western blot analysis. T139R mutation may expose the buried regions of TTR protein which help in the self association and the increase in the stability may help in the TTR deposition. Structural analysis indicated that F and H strands of TTR are more prone to aggregation. Thus, T139R mutation might cause these residues to be aggregation prone and change in folding rate and validated TTR monomer in diseased cases by Western blot analysis. The observed results clearly indicated that the occurrence of this mutation is causing the impact on the structural and functional significance of TTR by interfering in the formation of tetramer. Thus, hindrance created to thyroxin transportation resulted in higher lipid levels in the blood that ultimately might promote the progression of the CAD.


Effect of hydrogen-rich saline on apoptosis induced by hepatic ischemia reperfusion upon laparoscopic hepatectomy in miniature pigs.
Hepatic ischemia reperfusion injury (HIRI) occurs commonly in liver surgery and liver transplantation. Hydrogen, a safe and effective antioxidant, exerts a protective effect against liver injury. In this study, we investigated the role of hydrogen-rich saline (HRS) in apoptosis in a miniature pig model of laparoscopic HIRI upon hepatectomy. Bama miniature pigs were randomly assigned to sham, I/R and HRS groups. The pigs received 10 mL/kg HRS by portal venous injection 10 min before reperfusion and at 1 d, 2 d, and 3 d after surgery. The results showed that HRS treatment significantly decreased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) activity and TUNEL-positive cells. Upon HRS treatment, the expression of P53 and Bax mRNA and protein by RT-qPCR and Western blot was markedly decreased, whereas the expression of bcl-2 mRNA and protein was significantly increased. Moreover, Caspase-3 and Caspase-9 activities were significantly decreased upon treatment with HRS. In conclusion, the results indicate that HRS could alleviate liver injury and improve liver function via inhibiting apoptosis after laparoscopic HIRI and hepatectomy injury in miniature pigs.


Prevalence and prognostic importance of hypomagnesemia and hypocalcemia in horses that have colic surgery.
To determine the prevalence of hypomagnesemia and hypocalcemia in horses with surgical colic. 35 horses with surgically managed colic. Serum concentrations of total magnesium (tMg2+) and calcium (tCa2+), as well as ionized magnesium (iMg2+) and calcium (iCa2+) were analyzed before surgery and 1, 3, 5, and 7 days following surgery. A lead-II ECG and pertinent clinical data were also obtained at each time. Preoperative serum tMg2+ and iMg2+ concentrations were below the reference range in 6 (17%) and 19 (54%) horses, respectively. Serum concentrations of tCa2+ and iCa2+ were less than the reference range in 20 (57%) and 30 (86%) horses before surgery. Horses with strangulating lesions of the gastrointestinal tract had significantly lower preoperative serum concentrations of iMg2+ and iCa2+, as well as a higher heart rate than horses with nonstrangulating lesions. Horses that developed postoperative ileus had significantly lower serum concentrations of iMg2+ after surgery. Serum concentrations of magnesium and calcium (total and ionized) correlated significantly with the PR, QRS, QT, and corrected QT (QTc) intervals. Horses that were euthanatized at the time of surgery (n = 7) had significantly lower preoperative serum concentrations of iMg2+, compared with horses that survived. Neither serum magnesium nor calcium concentrations were predictors of hospitalization time or survival. Hypomagnesemia and hypocalcemia were common during the perioperative period, particularly in horses with strangulating intestinal lesions and ileus. Serum concentrations of tMg2+ and tCa2+ were less sensitive than iMg2+ and iCa2+ in detecting horses with hypomagnesemia and hypocalcemia.


Frequent inactivation of SPARC by promoter hypermethylation in colon cancers.
Epigenetic modification of gene expression plays an important role in the development of human cancers. The inactivation of SPARC through CpG island methylation was studied in colon cancers using oligonucleotide microarray analysis and methylation specific PCR (MSP). Gene expression of 7 colon cancer cell lines was evaluated before and after treatment with the demethylating agent 5-aza-2'-deoxycytidine (5Aza-dC) by oligonucleotide microarray analysis. Expression of SPARC was further examined in colon cancer cell lines and primary colorectal cancers, and the methylation status of the SPARC promoter was determined by MSP. SPARC expression was undetectable in 5 of 7 (71%) colorectal cancer cell lines. Induction of SPARC was demonstrated after treatment with the demethylating agent 5Aza-dC in 5 of the 7 cell lines. We examined the methylation status of the CpG island of SPARC in 7 colon cancer cell lines and in 20 test set of colon cancer tissues. MSP demonstrated hypermethylation of the CpG island of SPARC in 6 of 7 cell lines and in all 20 primary colon cancers, when compared with only 3 of 20 normal colon mucosa. Immunohistochemical analysis showed that SPARC expression was downregulated or absent in 17 of 20 colon cancers. A survival analysis of 292 validation set of colorectal carcinoma patients revealed a poorer prognosis for patients lacking SPARC expression than for patients with normal SPARC expression (56.79% vs. 75.83% 5-year survival rate, p = 0.0014). The results indicate that epigenetic gene silencing of SPARC is frequent in colon cancers, and that inactivation of SPARC is related to rapid progression of colon cancers.


Neurocognitive characterizations of Russian heroin addicts without a significant history of other drug use.
Research on the neurocognitive characteristics of heroin addiction is sparse and studies that do exist include polydrug abusers; thus, they are unable to distinguish neurocognitive effects of heroin from those of other drugs. To identify neurocognitive correlates specific to heroin addiction, the present study was conducted in St. Petersburg, Russia where individuals typically abuse and/or become addicted to only one substance, generally alcohol or heroin. Heroin addicts were recruited from an inpatient treatment facility in St. Petersburg. Three comparison groups included alcoholics, addicts who used both alcohol and heroin, and non-abusers. Psychiatric, background, and drug history evaluations were administered after detoxification to screen for exclusion criteria and characterize the sample. Executive Cognitive Functions (ECF) that largely activate areas of the prefrontal cortex and its circuitry measured include complex visual pattern recognition (Paired Associates Learning), working memory (Delayed Matching to Sample), problem solving (Stockings of Cambridge), executive decision making (Cambridge Decision Making Task), cognitive flexibility (Stroop Color-Word Task) and response shifting (Stop Change Task). In many respects, the heroin addicts were similar to alcohol and alcohol+heroin dependent groups in neurocognitive deficits relative to controls. The primary finding was that heroin addicts exhibited significantly more disadvantageous decision making and longer deliberation times while making risky decisions than the other groups. Because the nature and degree of recovery from drug abuse are likely a function of the type or pattern of neurocognitive impairment, differential drug effects must be considered.


Bessel-Gauss beam enhancement cavities for high-intensity applications.
We introduce Bessel-Gauss beam enhancement cavities that may circumvent the major obstacles to more efficient cavity-enhanced high-field physics such as high-harmonic generation. The basic properties of Bessel-Gauss beams are reviewed and their transformation properties through simple optical systems (consisting of spherical and conical elements) are presented. A general Bessel-Gauss cavity design strategy is outlined, and a particular geometry, the confocal Bessel-Gauss cavity, is analyzed in detail. We numerically simulate the confocal Bessel-Gauss cavity and present an example cavity with 300 MHz repetition rate supporting an effective waist of 33 μm at the focus and an intensity ratio from the focus to the cavity mirror surfaces of 1.5 × 10(4).


In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells.
Oncogenic signaling in melanocytes results in oncogene-induced senescence (OIS), a stable cell-cycle arrest frequently characterized by a bi- or multinuclear phenotype that is considered as a barrier to cancer progression. However, the long-sustained conviction that senescence is a truly irreversible process has recently been challenged. Still, it is not known whether cells driven into OIS can progress to cancer and thereby pose a potential threat. Here, we show that prolonged expression of the melanoma oncogene N-RAS(61K) in pigment cells overcomes OIS by triggering the emergence of tumor-initiating mononucleated stem-like cells from senescent cells. This progeny is dedifferentiated, highly proliferative, anoikis-resistant and induces fast growing, metastatic tumors. Our data describe that differentiated cells, which are driven into senescence by an oncogene, use this senescence state as trigger for tumor transformation, giving rise to highly aggressive tumor-initiating cells. These observations provide the first experimental in vitro evidence for the evasion of OIS on the cellular level and ensuing transformation.


Consumption of Meat, Fish, Dairy Products, and Eggs and Risk of Ischemic Heart Disease.
There is uncertainty about the relevance of animal foods to the pathogenesis of ischemic heart disease (IHD). We examined meat, fish, dairy products, and eggs and risk for IHD in the pan-European EPIC cohort (European Prospective Investigation Into Cancer and Nutrition). In this prospective study of 409 885 men and women in 9 European countries, diet was assessed with validated questionnaires and calibrated with 24-hour recalls. Lipids and blood pressure were measured in a subsample. During a mean of 12.6 years of follow-up, 7198 participants had a myocardial infarction or died of IHD. The relationships of animal foods with risk were examined with Cox regression with adjustment for other animal foods and relevant covariates. The hazard ratio (HR) for IHD was 1.19 (95% CI, 1.06-1.33) for a 100-g/d increment in intake of red and processed meat, and this remained significant after exclusion of the first 4 years of follow-up (HR, 1.25 [95% CI, 1.09-1.42]). Risk was inversely associated with intakes of yogurt (HR, 0.93 [95% CI, 0.89-0.98] per 100-g/d increment), cheese (HR, 0.92 [95% CI, 0.86-0.98] per 30-g/d increment), and eggs (HR, 0.93 [95% CI, 0.88-0.99] per 20-g/d increment); the associations with yogurt and eggs were attenuated and nonsignificant after exclusion of the first 4 years of follow-up. Risk was not significantly associated with intakes of poultry, fish, or milk. In analyses modeling dietary substitutions, replacement of 100 kcal/d from red and processed meat with 100 kcal/d from fatty fish, yogurt, cheese, or eggs was associated with ≈20% lower risk of IHD. Consumption of red and processed meat was positively associated with serum non-high-density lipoprotein cholesterol concentration and systolic blood pressure, and consumption of cheese was inversely associated with serum non-high-density lipoprotein cholesterol. Risk for IHD was positively associated with consumption of red and processed meat and inversely associated with consumption of yogurt, cheese, and eggs, although the associations with yogurt and eggs may be influenced by reverse causation bias. It is not clear whether the associations with red and processed meat and cheese reflect causality, but they were consistent with the associations of these foods with plasma non-high-density lipoprotein cholesterol and for red and processed meat with systolic blood pressure, which could mediate such effects.


α-lipoic acid reduces postreperfusion syndrome in human liver transplantation - a pilot study.
A double-blind randomized controlled trial was performed to compare the safety and efficacy of α-lipoic acid (ALA) in liver transplantation (LT). The grafts were randomized to receive ALA or placebo before the cold ischemia time. Furthermore, patients transplanted with the ALA-perfused graft received 600 mg of intravenous ALA, while patients with the nonperfused graft received the placebo just before graft reperfusion. Hepatic biopsy was performed 2 h postreperfusion. Blood samples were collected before, during and 1 and 2 days after reperfusion. Quantitative polymerase chain reaction (qPCR) analysis was performed on biopsies to assess genes involved in the response to hypoxia, apoptosis, cell growth, survival and proliferation, cytokine production and tissue damage protection. Nine of 40 patients developed postreperfusion syndrome (PRS), but seven of them belonged to the control group. There was a decrease in PHD2 and an increase in alpha subunit of hypoxia-inducible factor-1 (HIF-1α) and baculoviral IAP repeat containing 2 (Birc2) transcript levels in the biopsies from the ALA-treated versus the control group of patients. Additionally, plasma levels of alarmins were lower in ALA-treated patients than control patients, which suggests that ALA-treated grafts are less inflammatory than untreated grafts. These results showed that ALA is safe for use in LT, induces gene changes that protect against hypoxia and oxidative stress and reduces the appearance of PRS.


The Prospective Urban Rural Epidemiology (PURE) study: examining the impact of societal influences on chronic noncommunicable diseases in low-, middle-, and high-income countries.
Marked changes in the prevalence of noncommunicable diseases such as obesity, diabetes, and cardiovascular disease have occurred in developed and developing countries in recent decades. The overarching aim of the study is to examine the relationship of societal influences on human lifestyle behaviors, cardiovascular risk factors, and incidence of chronic noncommunicable diseases. The Prospective Urban Rural Epidemiology (PURE) study is a large-scale epidemiological study that plans to recruit approximately 140,000 individuals residing in >600 communities in 17 low-, middle-, and high-income countries around the world. Individual data collection includes medical history, lifestyle behaviors (physical activity and dietary profile), blood collection and storage for biochemistry and future genetic analysis, electrocardiogram, and anthropometric measures. In addition, detailed information is being collected with respect to 4 environmental domains of interest-the built environment, nutrition and associated food policy, psychosocial/socioeconomic factors, and tobacco environment. A minimum follow-up of 10 years is currently planned. This report describes the design, justification, and methodology of the PURE study. The PURE study has been recruiting since 2002 and has enrolled 139,506 individuals by March 31, 2009. The PURE study builds on the work and experience gained through conduct of the INTERHEART study. Its design and extensive data collection are geared toward addressing major questions on causation and development of the underlying determinants of cardiovascular disease in populations at varying stages of epidemiologic transition.


Dorsal Atlantoaxial Ligament Hypertrophy as a Cause for Clinical Signs in Dogs with Dens Abnormalities.
The objective of this study is to suggest clinical and subclinical atlantoaxial (AA) instability as a cause for dorsal AA ligament hypertrophy responsible for clinical signs in dogs with dens abnormalities. Clinical information from five dogs with malformed dens and dorsal spinal cord compression at the AA junction was collected. All dogs had neck pain, associated with tetraparesis in three cases. Radiological examination revealed hypoplastic dens in two dogs and a defect in its ossification in the other three. Stress views were able to demonstrate obvious AA instability only in two cases, but it was suspected in the other owing to response to surgical fixation of the joint and the presence of a dorsal compressive band, which was considered an enlarged dorsal AA ligament. Surgical and histopathological examination of compressive tissue confirmed hypertrophy of the ligament. Long-term prognosis in the four operated cases, either by dorsal decompression and ventral fixation or by ventral fixation alone, was excellent. A malformed dens can cause subclinical instability, unnoted in dynamic studies. As instability may lead to hypertrophy of joint ligaments, soft tissue changes (specifically dorsal AA ligament hypertrophy) points out this instability and the need for joint fixation if surgical management is required.


Global burden of respiratory infections associated with seasonal influenza in children under 5 years in 2018: a systematic review and modelling study.
Seasonal influenza virus is a common cause of acute lower respiratory infection (ALRI) in young children. In 2008, we estimated that 20 million influenza-virus-associated ALRI and 1 million influenza-virus-associated severe ALRI occurred in children under 5 years globally. Despite this substantial burden, only a few low-income and middle-income countries have adopted routine influenza vaccination policies for children and, where present, these have achieved only low or unknown levels of vaccine uptake. Moreover, the influenza burden might have changed due to the emergence and circulation of influenza A/H1N1pdm09. We aimed to incorporate new data to update estimates of the global number of cases, hospital admissions, and mortality from influenza-virus-associated respiratory infections in children under 5 years in 2018. We estimated the regional and global burden of influenza-associated respiratory infections in children under 5 years from a systematic review of 100 studies published between Jan 1, 1995, and Dec 31, 2018, and a further 57 high-quality unpublished studies. We adapted the Newcastle-Ottawa Scale to assess the risk of bias. We estimated incidence and hospitalisation rates of influenza-virus-associated respiratory infections by severity, case ascertainment, region, and age. We estimated in-hospital deaths from influenza virus ALRI by combining hospital admissions and in-hospital case-fatality ratios of influenza virus ALRI. We estimated the upper bound of influenza virus-associated ALRI deaths based on the number of in-hospital deaths, US paediatric influenza-associated death data, and population-based childhood all-cause pneumonia mortality data in six sites in low-income and lower-middle-income countries. In 2018, among children under 5 years globally, there were an estimated 109·5 million influenza virus episodes (uncertainty range [UR] 63·1-190·6), 10·1 million influenza-virus-associated ALRI cases (6·8-15·1); 870 000 influenza-virus-associated ALRI hospital admissions (543 000-1 415 000), 15 300 in-hospital deaths (5800-43 800), and up to 34 800 (13 200-97 200) overall influenza-virus-associated ALRI deaths. Influenza virus accounted for 7% of ALRI cases, 5% of ALRI hospital admissions, and 4% of ALRI deaths in children under 5 years. About 23% of the hospital admissions and 36% of the in-hospital deaths were in infants under 6 months. About 82% of the in-hospital deaths occurred in low-income and lower-middle-income countries. A large proportion of the influenza-associated burden occurs among young infants and in low-income and lower middle-income countries. Our findings provide new and important evidence for maternal and paediatric influenza immunisation, and should inform future immunisation policy particularly in low-income and middle-income countries. WHO; Bill & Melinda Gates Foundation.


Family-centered delirium prevention and treatment using video calls: the FACE Delirium trial.
In the FACE Delirium trial, we investigated the feasibility of a structured FAmily-CEntered delirium prevention and treatment during the corona pandemic. Patients hospitalized in a German geriatric medicine department were included in this single-center, prospective, single-arm feasibility study. Their relatives received a short training on delirium and volunteers or paid staff members facilitated video calls. The primary endpoint was reached when contact between patients and their relatives occurred on ≥ 80% of treatment days, either via video call or visit. 38 patients were included (age 83.0 ± 5.9 years; 73.7% women). 76.3% reached the primary endpoint. Due to the pandemic, 99.3% of the contacts were video calls with a duration of 24.8 ± 16.3 min. Family-centered delirium prevention and treatment using video calls is feasible among hospitalized geriatric patients. Daily implementation in clinical practice poses challenges and requires motivated and qualified staff.


Effect of longer health service provider delays on stage at diagnosis and mortality in symptomatic breast cancer.
This study explored whether longer provider delays (between first presentation and treatment) were associated with later stage and poorer survival in women with symptomatic breast cancer. Data from 850 women with symptomatic breast cancer were linked with the Scottish Cancer Registry; Death Registry; and hospital discharge dataset. Logistic regression and Cox survival analyses with restricted cubic splines explored relationships between provider delays, stage and survival, with sequential adjustment for patient and tumour factors. Although confidence intervals were wide in both adjusted analyses, those with the shortest provider delays had more advanced breast cancer at diagnosis. Beyond approximately 20 weeks, the trend suggests longer delays are associated with more advanced stage, but is not statistically significant. Those with symptomatic breast cancer and the shortest presentation to treatment time (within 4 weeks) had the poorest survival. Longer time to treatment was not significantly associated with worsening mortality. Poor prognosis patients with breast cancer are being triaged for rapid treatment with limited effect on outcome. Prolonged time to treatment does not appear to be strongly associated with poorer outcomes for patients with breast cancer, but the power of this study to assess the effect of very long delays (>25 weeks) was limited. Efforts to reduce waiting times are important from a quality of life perspective, but tumour biology may often be a more important determinant of stage at diagnosis and survival outcome.


Visualization of bond rearrangements in acetylene using near single-cycle laser pulses.
The migration of hydrogen atoms resulting in the isomerization of hydrocarbons is an important process which can occur on ultrafast timescales. Here, we visualize the light-induced hydrogen migration of acetylene to vinylidene in an ionic state using two synchronized 4 fs intense laser pulses. The first pulse induces hydrogen migration, and the second is used for monitoring transient structural changes via Coulomb explosion imaging. Varying the time delay between the pulses reveals the migration dynamics with a time constant of 54 ± 4 fs as observed in the H+ + H+ + CC+ channel. Due to the high temporal resolution, vibrational wave-packet motions along the CC- and CH-bonds are observed. Even though a maximum in isomerization yield for kinetic energy releases above 16 eV is measured, we find no indication for a backwards isomerization - in contrast to previous measurements. Here, we propose an alternative explanation for the maximum in isomerization yield, namely the surpassing of the transition state to the vinylidene configuration within the excited dication state.


A proposal for an evaluation model of pharmaceutical services for malaria.
Malaria is a serious public health problem in over 90 countries worldwide. In Brazil the disease is prevalent in the Amazon and the control rationale is based on early diagnosis and treatment. Quality pharmaceutical services are considered a key element for control. A proposal for evaluating pharmaceutical services for malaria is presented here. A theoretical outline composed of a logical model and an indicator framework is discussed and strives to establish a basis for assessment and judgment of the way in which these services are actually delivered. The aim is to contribute to the understanding of pharmaceutical services for malaria and other endemic diseases, complying with the directives of the Brazilian National Medicines Policy.


metID: an R package for automatable compound annotation for LC-MS-based data.
Accurate and efficient compound annotation is a long-standing challenge for LC-MS-based data (e.g. untargeted metabolomics and exposomics). Substantial efforts have been devoted to overcoming this obstacle, whereas current tools are limited by the sources of spectral information used (in-house and public databases) and are not automated and streamlined. Therefore, we developed metID, an R package that combines information from all major databases for comprehensive and streamlined compound annotation. metID is a flexible, simple and powerful tool that can be installed on all platforms, allowing the compound annotation process to be fully automatic and reproducible. A detailed tutorial and a case study are provided in Supplementary Materials. https://jaspershen.github.io/metID. Supplementary data are available at Bioinformatics online.


Selective arc-discharge synthesis of Dy2S-clusterfullerenes and their isomer-dependent single molecule magnetism.
A method for the selective synthesis of sulfide clusterfullerenes Dy2S@C2n is developed. Addition of methane to the reactive atmosphere reduces the formation of empty fullerenes in the arc-discharge synthesis, whereas the use of Dy2S3 as a source of metal and sulfur affords sulfide clusterfullerenes as the main fullerene products along with smaller amounts of carbide clusterfullerenes. Two isomers of Dy2S@C82 with Cs(6) and C3v(8) cage symmetry, Dy2S@C72-Cs(10528), and a carbide clusterfullerene Dy2C2@C82-Cs(6) were isolated. The molecular structure of both Dy2S@C82 isomers was elucidated by single-crystal X-ray diffraction. SQUID magnetometry demonstrates that all of these clusterfullerenes exhibit hysteresis of magnetization, with Dy2S@C82-C3v(8) being the strongest single molecule magnet in the series. DC- and AC-susceptibility measurements were used to determine magnetization relaxation times in the temperature range from 1.6 K to 70 K. Unprecedented magnetization relaxation dynamics with three consequent Orbach processes and energy barriers of 10.5, 48, and 1232 K are determined for Dy2S@C82-C3v(8). Dy2S@C82-Cs(6) exhibits faster relaxation of magnetization with two barriers of 15.2 and 523 K. Ab initio calculations were used to interpret experimental data and compare the Dy-sulfide clusterfullerenes to other Dy-clusterfullerenes. The smallest and largest barriers are ascribed to the exchange/dipolar barrier and relaxation via crystal-field states, respectively, whereas an intermediate energy barrier of 48 K in Dy2S@C82-C3v(8) is assigned to the local phonon mode, corresponding to the librational motion of the Dy2S cluster inside the carbon cage.


Distance-adjusted motor threshold for transcranial magnetic stimulation.
To examine the relationship between coil-cortex distance and effective cortical stimulation using transcranial magnetic stimulation (TMS) in the left and right motor cortex. We also compare the effect of coil-cortex distance using 50 and 70 mm figure-eight stimulating coils. Coil-cortex distance was manipulated within each participant using 5 and 10 mm acrylic separators placed between the coil and scalp surface. The effect of cortical stimulation was indexed by resting motor threshold (MT). Increasing distance between the coil and underlying cortex was associated with a steep linear increase in MT. For each additional millimetre separating the stimulating coil from the scalp surface, an additional approximately 2.8% of absolute stimulator output (approximately 0.062 T) was required to reach MT. The gradient of the observed distance effect did not differ between hemispheres, and no differences were observed between the 50 and 70 mm TMS coils. Coil-cortex distance directly influences the magnitude of cortical stimulation in TMS. The relationship between TMS efficacy and coil-cortex distance is well characterised by a linear function, providing a simple and effective method for scaling stimulator output to a distance adjusted MT. MT measured at the scalp-surface is dependent on the underlying scalp-cortex distance, and therefore does not provide an accurate index of cortical excitability. Distance-adjusted MT provides a more accurate index of cortical excitability, and improves the safety and efficacy of MT-calibrated TMS.


Magneto-optical tweezers built around an inverted microscope.
We present a simple experimental setup of magneto-optical tweezers built around an inverted microscope. Two pairs of coils placed around the focal point of the objective generate a planar-rotating magnetic field that is perpendicular to the stretching direction. This configuration allows us to control the rotary movement of a paramagnetic bead trapped in the optical tweezers. The mechanical design is universal and can be simply adapted to any inverted microscope and objective. The mechanical configuration permits the use of a rather large experimental cell and the simple assembly and disassembly of the magnetic attachment.


Running economy in early and late maturing youth soccer players does not differ.
The aim of this study was to investigate the influence of maturity on running economy in a population of young soccer players. 13 boys (mean age 14.3 years) active in soccer were divided into two groups: 6 early and 7 late maturers. Anthropometrical characteristics, respiratory exchange ratio, heart rate and maximal oxygen uptake were measured. Running economy was assessed at three submaximal running speeds (8, 9.5 and 11 km/h). Allometric coefficients were calculated and used to diminish the effect of body mass. In addition, running style was analysed biomechanically (stride length and meaningful kinematic values). There was no significant difference in the running economy of early and late maturing soccer players, nor any significant differences in mass adjusted physiological values. Therefore physiological differences cannot explain why late maturers succeed in keeping up with early maturers. Late maturing boys take longer relative strides, and have more anteversion of the thigh at heel contact, a smaller knee-angle during swing-phase and a lower mass moment of inertia. Running style seems to be an important determinant in running economy of children.


First Report of Homothallic Isolates of Phytophthora infestans in Commercial Potato Crops (Solanum tuberosum) in the Toluca Valley, Mexico.
Phytophthora infestans causes severe symptoms of wilt disease on potato crops (Solanum tuberosum) in the Toluca Valley (Mexico) despite the use of fungicides. P. infestans oospores produced by sexual reproduction can survive in the soil for many years, resisting harsh environments. In many agroecosystems, oospores germinate in the beginning of a season, which represents the initial inoculum for epidemics. The sexual cycle of the pathogen allows the generation of recombinant genotypes that can be more pathogenic or even resistant to chemicals. This paper presents a study of 20 isolates of P. infestans collected from potato crops in the Toluca Valley within the municipality of Zinacantepec (Mexico State). Isolates were obtained from potato foliar infected tissues. The pathogen was confirmed as P. infestans on the basis of morphological characters (1). Sporangia were caducous, ovoid, limoniform, semipapillate, and were 28.4 ± 1.3 × 17.6 ± 1.2 μm (height × width). Mycelium was coenocytic with hyphal diameter of 5 to 8 μm. Five isolates were collected in 2011, and 15 in 2012. Isolates were transferred by hyphal tip to culture medium plates with V8 juice agar and incubated at 19°C. All the isolates were mated to determine the mating type with the reference isolates J104 (A1) and J204 (A2), which were provided by the Michoacana University of San Nicolás de Hidalgo (Mx). Isolates that produced oospores with both A1 and A2 testers (J104 and J204) and in a single culture were designated homothallic. Results show that two out of the five isolates collected in 2011 were homothallic and the other three were type A1. Regarding the 15 isolates collected in 2012, six were typed as A1, five as A2, and four were homothallic. The heterothallic isolates only produce oospores when mated with the opposite mating type. The homothallic isolates possessed the ability to act as A1 and A2 during heterothallic mating and were found capable of producing sexual structures (oogonia and amphigynous antheridia) in a single culture, a phenomenon not observed in isolates that are strictly A1 or A2. Oospores formed were aplerotic and measured 32.2 ± 3.3 μm in diameter. Single-sporangium progeny were produced from the six homothallic isolates to be analyzed to confirm the occurrence of the self-fertility. Assessment of 48 single-sporangium progeny from the homothallic isolates resulted in 22 homothallic, 12 A1, 10 A2, and four sterile. These results differ from those found by Grünwald et al. (3), who conducted a study with isolates collected from the Toluca Valley region in 1997 and 1998, finding a 1:1 frequency between compatibility types A1 and A2. Fernandez et al. (2) studied a broad population of 27 isolates from potato crops in the state of Michoacán (Mx), and found two homothallic isolates among heterothallic isolates; the ratio was 1:1. Also, homothallic isolates have been found in Spain and China (4). To our knowledge, this is the first report of the occurrence of homothallic P. infestans isolates in commercial potato crops (S. tuberosum) in the Toluca Valley, Mexico. References: (1) D. C. Erwin and O. K. Ribeiro, Page 346 in: Phytophthora Diseases Worldwide. The American Phytopathological Society. St. Paul, MN, 1996. (2) S. P. Fernández et al. Rev. Mexicana Fitopatol. 23:191, 2005. (3) N. J. Grünwald et al. Phytopathology 91:883, 2001. (4) M. Han et al. J. Eukaryotic Microbiol. 60:79, 2013.


Rapid conversion of Pseudomonas aeruginosa to a spherical cell morphotype facilitates tolerance to carbapenems and penicillins but increases susceptibility to antimicrobial peptides.
The Gram-negative human pathogen Pseudomonas aeruginosa tolerates high concentrations of β-lactam antibiotics. Despite inhibiting the growth of the organism, these cell wall-targeting drugs exhibit remarkably little bactericidal activity. However, the mechanisms underlying β-lactam tolerance are currently unclear. Here, we show that P. aeruginosa undergoes a rapid en masse transition from normal rod-shaped cells to viable cell wall-defective spherical cells when treated with β-lactams from the widely used carbapenem and penicillin classes. When the antibiotic is removed, the entire population of spherical cells quickly converts back to the normal bacillary form. Our results demonstrate that these rapid population-wide cell morphotype transitions function as a strategy to survive antibiotic exposure. Taking advantage of these findings, we have developed a novel approach to efficiently kill P. aeruginosa by using carbapenem treatment to induce en masse transition to the spherical cell morphotype and then exploiting the relative fragility and sensitivity of these cells to killing by antimicrobial peptides (AMPs) that are relatively inactive against P. aeruginosa bacillary cells. This approach could broaden the repertoire of antimicrobial compounds used to treat P. aeruginosa and serve as a basis for developing new therapeutic agents to combat bacterial infections.


Comparison of two epinephrine concentrations in an articaine solution for local anesthesia in children.
Painless dental treatment is of major interest in pediatric dentistry. Local anesthesia contains epinephrine, which prolongs soft tissue anesthesia.This, however, is often a source of iscomfort for children and is responsible for certain side effects (e.g., self-inflicted soft tissue lesions). The aim of this study was to investigate whether an epinephrine-reduced articaine solution could reduce the duration of soft tissue anesthesia and thereby reduce the risk of self-inflicted soft tissue lesions, while still providing an adequate anesthesia. In a non-interventional clinical study, routine dental treatment was performed on children and adolescents. An articaine 4% solution with an epinephrine-reduced solution (Ubistesin™ mite, 1:400,000) and a conventional epinephrine solution (Ubistesin™ forte, 1:100,000) were compared in terms of duration of soft tissue anesthesia. One hundred and fifty-eight patients (mite: 75, forte: 83) were treated (80% with infiltration anesthesia). In both groups, the average volume of the injection was comparable (mite: 1.2 ml, forte: 1.1 ml). One patient from each group showed unwanted side effects. In both groups, the local anesthesia was complete or sufficient (96%) to perform the planned treatment. The average treatment time was 24 minutes in the mite group and 28 minutes in the forte group. The difference in mean duration of soft tissue anesthesia was statistically significant (p = 0.001, mite: 2.1 h, forte: 2.8 h). Thanks to its high efficacy, tolerance, and reduced soft tissue anesthesia, the articaine 4% solution with the reduced epinephrine concentration (1:400,000) was considered a safe and suitable drug for routine treatments in pediatric dentistry.


Alterations in the basement membrane zone in pili annulati hair follicles as demonstrated by electron microscopy and immunohistochemistry.
Pili annulati is a rare autosomal dominant inherited hair shaft abnormality in which clinical examination reveals alternating light and dark bands leading to a shiny appearance of the hair. The clinically light bands are the abnormal areas due to cavities within the cortex. The pathogenesis remains unknown. To investigate the expression of the basement membrane zone (BMZ) components in pili annulati hair follicles of the scalp. Transmission electron microscopy (TEM) was carried out on scalp sections of six individuals with pili annulati and six controls. Longitudinal sections of scalp tissues from four individuals with pili annulati and six normal controls were studied by immunohistochemistry with a panel of monoclonal antibodies to the following BMZ components: alpha(6)beta(4) integrin, laminin 5, LH39 antigen, laminin 1, collagen IV and collagen VII. Using TEM, pili annulati scalp specimens exhibited a reduplicated lamina densa in the region of the root bulb in comparison with the single thin electron-dense band in controls. Using immunohistochemistry, there was a wavy BMZ in pili annulati follicles with antibodies to components of the lamina lucida, lamina densa and anchoring fibrils, whereas the BMZ in control hair follicles was as a smooth linear band. The expression of the hemidesmosome-associated alpha(6)beta(4) integrin was linear in both pili annulati and control hair follicles. Our results suggest that the genetic defect may be a mutation in proteins involved in signalling and regulation of formation and degradation of the lamina densa and sublamina densa region resulting in abnormal assembly or remodelling of the BMZ.


TPC2-mediated Ca2+ signaling is required for the establishment of synchronized activity in developing zebrafish primary motor neurons.
During the development of the early spinal circuitry in zebrafish, spontaneous Ca2+ transients in the primary motor neurons (PMNs) are reported to transform from being slow and uncorrelated, to being rapid, synchronized and patterned. In this study, we demonstrated that in intact zebrafish, Ca2+ release via two-pore channel type 2 (TPC2) from acidic stores/endolysosomes is required for the establishment of synchronized activity in the PMNs. Using the SAIGFF213A;UAS:GCaMP7a double-transgenic zebrafish line, Ca2+ transients were visualized in the caudal PMNs (CaPs). TPC2 inhibition via molecular, genetic or pharmacological means attenuated the CaP Ca2+ transients, and decreased the normal ipsilateral correlation and contralateral anti-correlation, indicating a disruption in normal spinal circuitry maturation. Furthermore, treatment with MS-222 resulted in a complete (but reversible) inhibition of the CaP Ca2+ transients, as well as a significant decrease in the concentration of the Ca2+ mobilizing messenger, nicotinic acid adenine diphosphate (NAADP) in whole embryo extract. Together, our new data suggest a novel function for NAADP/TPC2-mediated Ca2+ signaling in the development, coordination, and maturation of the spinal network in zebrafish embryos.


Loop variants of the serpin thyroxine-binding globulin: implications for hormone release upon limited proteolysis.
Thyroxine-binding globulin (TBG) and corticosteroid-binding globulin are unique among non-inhibitory members of the superfamily of serine-proteinase inhibitors (serpins) in undergoing a dramatic increase in stability [stressed-to-relaxed (S-->R) transition] after proteolytic cleavage within their exposed reactive-site-loop (RSL) equivalent. This structural rearrangement involves the insertion of the cleaved loop as a new strand into the beta-sheet A and is accompanied by a decrease in hormone binding. To define the mechanism that leads to disruption of hormone binding of TBG after proteolytic cleavage, the effect of partial loop deletions and replacements by the alpha(1)-proteinase inhibitor homologues of TBG were evaluated. Unexpectedly, deletion of the loop's C-terminus, thought to be important for thyroxine binding, improved the binding affinity over that of normal TBG. Proteolytic cleavage of this variant revealed an intact S-->R transition and reduced its binding activity to that of cleaved TBG. In contrast, a chimaera with C-terminal loop extension mimicked the decreased binding affinity of cleaved TBG and had a thermal stability intermediate between that of native and cleaved serpins. This variant was still susceptible to loop cleavage and underwent an S-->R transition, yet without changing its binding affinity. Our data exclude a direct involvement of loop residues in thyroxine binding of native TBG. Limited insertion of the RSL into beta-sheet A appears to trigger hormone release after proteolytic cleavage. In support of this concept, residues within the hinge region of the TBG loop are phylogenetically highly conserved, suggestive of their physiological role as a functional switch in vivo.


Surround facilitation for rapid motion perception.
Because we live in a dynamic environment with moving eyes and body, our retinas are often stimulated by new scenes that appear suddenly and are only briefly available. How the visual system successfully extracts information from such challenging stimulation is not yet understood. For some stimuli, like photos of natural scenes, we are accurate in detecting objects like animals or faces even when the stimulus is presented for a short time. For other stimuli, like noisy motion, previous studies have shown accurate perception only when the stimulus is presented for a long time--often longer than the typical available time of a stimulus in natural viewing. Here we show, however, that a transient surround can accelerate the perception of motion. We found that for briefly displayed random-dots, the signal necessary to detect motion is reduced from 19% to 8% when a task-irrelevant surround is presented in synchrony with the random-dots, while no improvement occurs when the surround is sustainedly presented, or when it is transiently, but asynchronously, presented. We also found that motion sensitivity increases steadily with duration when no surround is presented, confirming previous findings, but duration has little effect on sensitivity when a synchronous surround is presented. Further results indicate that the facilitation by a synchronous surround is related to relative-motion processing. Our findings suggest that spatial interactions might assist rapid perception of motion.


Nutritional behavior of cyclists during a 24-hour team relay race: a field study report.
Information about behavior of energy intake in ultra-endurance cyclists during a 24-hour team relay race is scarce. The nutritional strategy during such an event is an important factor which athletes should plan carefully before the race. The purpose of this study was to examine and compare the nutritional intake of ultra-endurance cyclists during a 24-hour team relay race with the current nutritional guidelines for endurance events. Additionally, we analyzed the relationship among the nutritional and performance variables. Using a observational design, nutritional intake of eight males (mean ± SD: 36.7 ± 4.7 years; 71.6 ± 4.9 kg; 174.6 ± 7.3 cm; BMI 23.5 ± 0.5 kg/m2) participating in a 24-hour team relay cycling race was assessed. All food and fluid intake by athletes were weighed and recorded. Additionally, distance and speed performed by each rider were also recorded. Furthermore, before to the race, all subjects carried out an incremental exercise test to determine two heart rate-VO2 regression equations which were used to estimate the energy expenditure. The mean ingestion of macronutrients during the event was 943 ± 245 g (13.1 ± 4.0 g/kg) of carbohydrates, 174 ± 146 g (2.4 ± 1.9 g/kg) of proteins and 107 ± 56 g (1.5 ± 0.7 g/kg) of lipids, respectively. This amount of nutrients reported an average nutrient intake of 22.8 ± 8.9 MJ which were significantly lower compared with energy expenditure 42.9 ± 6.8 MJ (P = 0.012). Average fluid consumption corresponded to 10497 ± 2654 mL. Mean caffeine ingestion was 142 ± 76 mg. Additionally, there was no relationship between the main nutritional variables (i.e. energy intake, carbohydrates, proteins, fluids and caffeine ingestion) and the main performance variables (i.e. distance and speed). A 24-hour hours cycling competition in a team relay format elicited high energy demands which were not compensated by energy intake of the athletes despite that dietary consumption of macronutrients did not differ to the nutritional guidelines for longer events.


Depression and risk of type 2 diabetes: the potential role of metabolic factors.
The aim of the present study was to evaluate the interaction between depressive symptoms and metabolic dysregulations as risk factors for type 2 diabetes. The sample comprised of 2525 adults who participated in a baseline and a follow-up assessment over a 4.5-year period in the Emotional Health and Wellbeing Study (EMHS) in Quebec, Canada. A two-way stratified sampling design was used, on the basis of the presence of depressive symptoms and metabolic dysregulation (obesity, elevated blood sugar, high blood pressure, high levels of triglycerides and decreased high-density lipoprotein). A total of 87 (3.5%) individuals developed diabetes. Participants with both depressive symptoms and metabolic dysregulation had the highest risk of diabetes (adjusted odds ratio=6.61, 95% confidence interval (CI): 4.86-9.01), compared with those without depressive symptoms and metabolic dysregulation (reference group). The risk of diabetes in individuals with depressive symptoms and without metabolic dysregulation did not differ from the reference group (adjusted odds ratio=1.28, 95% CI: 0.81-2.03), whereas the adjusted odds ratio for those with metabolic dysregulation and without depressive symptoms was 4.40 (95% CI: 3.42-5.67). The Synergy Index (SI=1.52; 95% CI: 1.07-2.17) suggested that the combined effect of depressive symptoms and metabolic dysregulation was greater than the sum of individual effects. An interaction between depression and metabolic dysregulation was also suggested by a structural equation model. Our study highlights the interaction between depressive symptoms and metabolic dysregulation as a risk factor for type 2 diabetes. Early identification, monitoring and a comprehensive management approach of both conditions might be an important diabetes prevention strategy.


Optical coherence tomography endoscopic probe based on a tilted MEMS mirror.
This paper reports a compact microendoscopic OCT probe with an outer diameter of only 2.7 mm. The small diameter is enabled by a novel 2-axis scanning MEMS mirror with a preset 45° tilted angle. The tilted MEMS mirror is directly integrated on a silicon optical bench (SiOB). The SiOB provides mechanical support and electrical wiring to the mirror plate via a set of bimorph flexure, enabling a compact probe mount design without the requirement of a 45° slope, which is capable to dramatically reduce the probe size and ease the assembly process. Additionally, the SiOB also provides trenches with properly-designed opening widths for automatic alignment of the MEMS mirror, GRIN lens and optical fiber. The 45°-tilted MEMS mirror plate is actuated by four electrothermal bimorph actuators. The packaged 2.7 mm-diameter probe offers 2-axis side-view optical scanning with a large optical scan range of 40° at a low drive voltage of 5.5 Vdc in both axes, allowing a lateral scan area of 2.2 mm × 2.2 mm at a 3 mm working distance. High-resolution 2D and 3D OCT images of the IR card, ex vivo imaging of meniscus specimens and rat brain slices, in vivo imaging of the human finger and nail have been obtained with a TDOCT system.


Renal injury from angiotensin II-mediated hypertension.
Angiotensin II (Ang II)-mediated hypertension induces vascular smooth muscle cell hypertrophy and hyperplasia in systemic blood vessels, but the effects of Ang II on the intrinsic cell populations within the kidney have been less well characterized. We infused Ang II for 14 days into rats by minipump at doses (200 ng/min) that resulted in moderate hypertension (mean systolic blood pressure 156-172 mm Hg). Small renal arterial vessels of Ang II-infused rats demonstrated focal injury with fibrinoid necrosis and medial hyperplasia, whereas the glomerular capillaries demonstrated only rare segmental hyalinosis. Proliferation of vascular smooth muscle cells was pronounced (fourfold to 20-fold increase in [3H]thymidine incorporation) as opposed to a minimal proliferation of glomerular cells in Ang II-infused rats. In contrast, the principal effect of Ang II in glomeruli was to increase the expression of alpha-smooth muscle actin by mesangial cells and desmin by visceral glomerular epithelial cells. Ang II-infused rats also developed focal tubulointerstitial injury, with tubular atrophy and dilation, cast formation, an interstitial monocytic infiltrate, and mild interstitial fibrosis with increased type IV collagen deposition. The injury was associated with a proliferation of distal tubule, collecting duct, and interstitial cells as determined by immunostaining for proliferating cell nuclear antigen, and was accompanied by an increase in platelet-derived growth factor B-chain messenger RNA in the area of interstitial injury as localized by in situ hybridization. Renal interstitial cells also underwent phenotypic modulation in which they expressed alpha-smooth muscle actin. Vehicle-infused control rats displayed no tubular injury, proliferation, or phenotypic modulation. Thus, Ang II in doses that cause moderate hypertension induces marked vascular, glomerular, and tubulointerstitial injury with cell proliferation, leukocyte recruitment, phenotypic modulation with the upregulation of proteins normally associated with smooth muscle cells, and interstitial fibrosis.


Multi-Invasion-Induced Rearrangements as a Pathway for Physiological and Pathological Recombination.
Cells mitigate the detrimental consequences of DNA damage on genome stability by attempting high fidelity repair. Homologous recombination templates DNA double-strand break (DSB) repair on an identical or near identical donor sequence in a process that can in principle access the entire genome. Other physiological processes, such as homolog recognition and pairing during meiosis, also harness the HR machinery using programmed DSBs to physically link homologs and generate crossovers. A consequence of the homology search process by a long nucleoprotein filament is the formation of multi-invasions (MI), a joint molecule in which the damaged ssDNA has invaded more than one donor molecule. Processing of MI joint molecules can compromise the integrity of both donor sites and lead to their rearrangement. Here, two mechanisms for the generation of rearrangements as a pathological consequence of MI processing are detailed and the potential relevance for non-allelic homologous recombination discussed. Finally, it is proposed that MI-induced crossover formation may be a feature of physiological recombination.


Is Laminar Cartilage Composition as Determined by T2 Relaxometry Associated with Incident and Worsening of Cartilage or Bone Marrow Abnormalities?
To test the hypothesis that superficial cartilage composition (T2) is associated with subsequent incidence or worsening of cartilage damage, and deep T2 with that of bone marrow lesions (BMLs) in knees without radiographic osteoarthritis (ROA). A total of 201 knees from the Osteoarthritis Initiative without ROA were included: 78 from the healthy reference cohort, 60 without ROA but with risk factors, and 63 without ROA but with contralateral ROA. Year 1 (Y1) superficial and deep cartilage T2 were derived in the medial and lateral (weightbearing) femur (MF/LF) and tibia (MT/LT), using sagittal multiecho spin echo magnetic resonance images. Cartilage and BMLs were assessed in the medial (MFTJ) and lateral femorotibial joint (LFTJ) at Y1 and 3 years later. Binary logistic regression statistics were applied. Incidence or worsening of cartilage damage was more frequent (MFTJ 15%, LFTJ 13%) than incidence or worsening of BMLs (6.0%, 4.5%). In knees with incident or worsening cartilage lesions in the MF and LT, deep layer T2 in the same plate was elevated (MF, 43.6 ± 4.0 vs. 41.3 ± 3.8 ms, P = 0.047; LT, 33.8 ± 2.3 vs. 32.0 ± 2.2 ms, P = 0.008) compared to those without. In knees with incident or worsening of BMLs in the LFTC and LT, superficial layer T2 was elevated (LFTJ, 49.6 ± 4.8 vs. 46.7 ± 3.1 ms; LT, 47.4 ± 4.9 vs. 44.0 ± 3.3 ms, both Ps = 0.04). Contrary to our hypothesis, increased deep layer cartilage T2 was associated with subsequent worsening of cartilage damage, whereas superficial layer T2 was related to subsequent BML worsening. Yet, this relationship was observed in some, but not in all cartilage plates.


Revising the measurement process in the variational quantum eigensolver: is it possible to reduce the number of separately measured operators?
Current implementations of the Variational Quantum Eigensolver (VQE) technique for solving the electronic structure problem involve splitting the system qubit Hamiltonian into parts whose elements commute within their single qubit subspaces. The number of such parts rapidly grows with the size of the molecule. This increases the computational cost and can increase uncertainty in the measurement of the energy expectation value because elements from different parts need to be measured independently. To address this problem we introduce a more efficient partitioning of the qubit Hamiltonian using fewer parts that need to be measured separately. The new partitioning scheme is based on two ideas: (1) grouping terms into parts whose eigenstates have a single-qubit product structure, and (2) devising multi-qubit unitary transformations for the Hamiltonian or its parts to produce less entangled operators. The first condition allows the new parts to be measured in the number of involved qubit consequential one-particle measurements. Advantages of the new partitioning scheme resulting in severalfold reduction of separately measured terms are illustrated with regard to the H2 and LiH problems.


Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice.
Defects of mitochondrial DNA (mtDNA) maintenance have recently been associated with inherited neurodegenerative and muscle diseases and the aging process. Twinkle is a nuclear-encoded mtDNA helicase, dominant mutations of which cause adult-onset progressive external ophthalmoplegia (PEO) with multiple mtDNA deletions. We have generated transgenic mice expressing mouse Twinkle with PEO patient mutations. Multiple mtDNA deletions accumulate in the tissues of these mice, resulting in progressive respiratory dysfunction and chronic late-onset mitochondrial disease starting at 1 year of age. The muscles of the mice faithfully replicate all of the key histological, genetic, and biochemical features of PEO patients. Furthermore, the mice have progressive deficiency of cytochrome c oxidase in distinct neuronal populations. These "deletor" mice do not, however, show premature aging, indicating that subtle accumulation of mtDNA deletions and progressive respiratory chain dysfunction are not sufficient to accelerate aging. This model is a valuable tool for therapy development and testing for adult-onset mitochondrial disorders.


Mitochondrial biogenesis during differentiation of Artemia salina cysts.
Mitochondria isolated from cysts of Artemia salina (brine shrimp) were found to be devoid of cristae and to possess a low respiratory capability. Hydration of the cysts induces marked biochemical and morphological changes in the mitochondria. Their biogenesis proceeds in two stages. The first stage is completed within 1 h and is characterized by a rapid increase in the respiratory capability of the mitochondria, their cytochrome oxidase, cytochrome b, cytochrome c and perhaps some morphological changes. In the second stage there is an increase in the protein-synthesizing capacity of the mitochondria as well as striking changes in mitochondrial morphology leading to the formation of cristae.


Failures of fractional crystallization: ordered co-crystals of isomers and near isomers.
A list of 270 structures of ordered co-crystals of isomers, near isomers and molecules that are almost the same has been compiled. Searches for structures containing isomers could be automated by the use of IUPAC International Chemical Identifier (InChI™) strings but searches for co-crystals of very similar molecules were more labor intensive. Compounds in which the heteromolecular A···B interactions are clearly better than the average of the homomolecular A···A and B···B interactions were excluded. The two largest structural classes found include co-crystals of configurational diastereomers and of quasienantiomers (or quasiracemates). These two groups overlap. There are 114 co-crystals of diastereomers and the same number of quasiracemates, with 71 structures being counted in both groups; together the groups account for 157 structures or 58% of the total. The large number of quasiracemates is strong evidence for inversion symmetry being very favorable for crystal packing. Co-crystallization of two diastereomers is especially likely if a 1,1 switch of a methyl group and an H atom, or of an inversion of a [2.2.1] or [2.2.2] cage, in one of the diastereomers would make the two molecules enantiomers.


Autoreactive epitopes defined by diabetes-associated human monoclonal antibodies are localized in the middle and C-terminal domains of the smaller form of glutamate decarboxylase.
The gamma-aminobutyrate-synthesizing enzyme glutamate decarboxylase (GAD; L-glutamate 1-carboxy-lyase, EC 184.108.40.206) is a major target of autoantibodies associated with both early and late stages of pancreatic beta-cell destruction and development of type 1 diabetes. We have used five monoclonal anti-islet-cell antibodies (MICAs 1,2,3,4, and 6) derived from a newly diagnosed diabetic patient to probe the autoimmune epitopes in the enzyme. All the MICAs specifically recognized the smaller GAD protein, GAD65, and did not recognize the nonallelic GAD67 protein. A series of N-terminal, C-terminal, and internal deletion mutants, as well as protein footprinting, were used to identify the target regions in GAD65. Immunoprecipitation revealed two major native epitope areas in the GAD65 molecule. The first, defined by MICAs 1 and 3, is destroyed by deleting 41 amino acids at the C terminus but is also dependent on intact amino acids 244-295. This epitope (or epitopes) may span both middle and C-terminal domains of the protein. The second conformational epitope region, defined by MICAs 4 and 6, is dependent on intact amino acids 245-295 but is not affected by deletion of 110 amino acids at the C terminus and is therefore confined to domain(s) in the middle of the molecule. MICA 2 recognizes a linear epitope close to the C terminus. Thus, the N-terminal domain of GAD65, which differs most significantly from GAD67, does not harbor the MICA epitopes. Rather subtle amino acid differences in the middle and C-terminal domains define the GAD65-specific autoimmune epitopes. Analysis of sera from 10 type 1 diabetic patients suggests that MICAs 1, 3, 4, and 6 represent a common epitope recognition in this disease, whereas the MICA 2 epitope is rare. Furthermore, autoantibodies in some sera are restricted to the MICA 1/3 epitope, suggesting that this epitope may represent a single dominant epitope in the early phases of beta-cell autoimmunity.


Common variants in RYR1 are associated with left ventricular hypertrophy assessed by electrocardiogram.
To identify the genetic risk factors that influence the development of electrocardiographic (ECG) left ventricular hypertrophy (LVH), a major risk factor for cardiovascular (CV) morbidity and mortality. We performed a genomewide association study (GWAS) of ECG-LVH, in which the community-based Korea Association REsource (KARE) study (8432 controls and 398 cases) was analysed by Affymetrix SNP array 5.0. The GWAS results were validated in hospital-based samples (597 controls and 207 cases). Fourteen single-nucleotide polymorphisms (SNPs) in eight genetic loci (5q35.1, 6p22.3-22.1, 8q24.2, 11p15, 11q21-22.1, 14q12, 17q11.2, and 19q13.1) were associated with ECG-LVH in the original GWAS study (P < 1 × 10(-5)). Of these SNPs, 12 were genotyped in the hospital sample. There was consistent association with the 19q13.1 region which contains RYR1 gene. The most significant SNP in the region was rs10500279, which had genomewide significance in the combined GWAS/replication sample [odds ratio = 1.58 (confidence interval: 1.35-1.85), P = 1.0 × 10(-8)]. Mutations in RYR1, which encodes a major Ca(2+) channel in the skeletal muscle, have been reported to correlate with CV diseases. We performed the first GWAS for ECG-LVH, implicating the skeletal muscle Ca(2+) channel protein RYR1 as a genetic risk factor. These results might increase our understanding of the development of ECG-LVH.


Deciphering the transport of elastic filaments by antagonistic motor proteins.
Intermediate filaments are long elastic fibers that are transported by the microtubule-associated motor proteins kinesin and dynein inside the cell. How elastic filaments are efficiently transported by antagonistic motors is not well understood and is difficult to measure with current experimental techniques. Adapting the tug-of-war paradigm for vesiclelike cargos, we develop a mathematical model to describe the motion of an elastic filament punctually bound to antagonistic motors. As observed in cells, up to three modes of transport are obtained; dynein-driven retrograde, kinesin-driven anterograde fast motions, and a slow motion. Motor properties and initial conditions that depend on intracellular context regulate the transport of filaments. Filament elasticity is found to affect both the mode and the efficiency of transport. We further show that the coordination of motors along the filament emerges from the interplay between intracellular context and elastic properties of filaments.


From mind wandering to involuntary retrieval: Age-related differences in spontaneous cognitive processes.
The majority of studies that have investigated the effects of healthy aging on cognition have focused on age-related differences in voluntary and deliberately engaged cognitive processes. Yet many forms of cognition occur spontaneously, without any deliberate attempt at engaging them. In this article we review studies that have assessed age-related differences in four such types of spontaneous thought processes: mind-wandering, involuntary autobiographical memory, intrusive thoughts, and spontaneous prospective memory retrieval. These studies suggest that older adults exhibit a reduction in frequency of both mind-wandering and involuntary autobiographical memory, whereas findings regarding intrusive thoughts have been more mixed. Additionally, there is some preliminary evidence that spontaneous prospective memory retrieval may be relatively preserved in aging. We consider the roles of age-related differences in cognitive resources, motivation, current concerns and emotional regulation in accounting for these findings. We also consider age-related differences in the neural correlates of spontaneous cognitive processes.


Academic effects of concussion in children and adolescents.
The aim of this work is to study the nature and extent of the adverse academic effects faced by students recovering from concussion. A sample of 349 students ages 5 to 18 who sustained a concussion and their parents reported academic concerns and problems (eg, symptoms interfering, diminished academic skills) on a structured school questionnaire within 4 weeks of injury. Postconcussion symptoms were measured as a marker of injury severity. Results were examined based on recovery status (recovered or actively symptomatic) and level of schooling (elementary, middle, and high school). Actively symptomatic students and their parents reported higher levels of concern for the impact of concussion on school performance (P < .05) and more school-related problems (P < .001) than recovered peers and their parents. High school students who had not yet recovered reported significantly more adverse academic effects than their younger counterparts (P < .05). Greater severity of postconcussion symptoms was associated with more school-related problems and worse academic effects, regardless of time since injury (P < .001). This study provides initial evidence for a concussion's impact on academic learning and performance, with more adverse effects reported by students who had not yet recovered from the injury. School-based management with targeted recommendations informed by postinjury symptoms may mitigate adverse academic effects, reduce parent and student concerns for the impact of the injury on learning and scholastic performance, and lower the risk of prolonged recovery for students with active postconcussion symptoms.


The association between antidepressant use and hemoglobin A1C in older adults.
Depression is known to increase diabetes risk and worsen glycemic control in older adults, who already experience high rates of diabetes. The independent impact of antidepressants on glucose control is less clear. Data was drawn from the Health and Retirement Study, a large nationally-representative longitudinal study of retired individuals. Crude and adjusted linear models stratified by diabetes status were used to examine the cross-sectional associations between antidepressant use categorized by subclass and continuous hemoglobin A1C. The sample included 1,153 individuals, most over the age of 70. Antidepressant use was not associated with hemoglobin A1C in any model whether stratified or in the total combined sample. Antidepressants as a class were also not associated with hemoglobin A1C. These findings add to the literature suggesting that antidepressants are not associated with diabetes risk or glycemic control. Prospective studies with larger sample sizes are needed to confirm this finding.


In vivo methylation of mtDNA reveals the dynamics of protein-mtDNA interactions.
To characterize the organization of mtDNA-protein complexes (known as nucleoids) in vivo, we have probed the mtDNA surface exposure using site-specific DNA methyltransferases targeted to the mitochondria. We have observed that DNA methyltransferases have different accessibility to different sites on the mtDNA based on the levels of protein occupancy. We focused our studies on selected regions of mtDNA that are believed to be major regulatory regions involved in transcription and replication. The transcription termination region (TERM) within the tRNA(Leu(UUR)) gene was consistently and strongly protected from methylation, suggesting frequent and high affinity binding of mitochondrial transcription termination factor 1 (mTERF1) to the site. Protection from methylation was also observed in other regions of the mtDNA, including the light and heavy strand promoters (LSP, HSP) and the origin of replication of the light strand (OL). Manipulations aiming at increasing or decreasing the levels of the mitochondrial transcription factor A (TFAM) led to decreased in vivo methylation, whereas manipulations that stimulated mtDNA replication led to increased methylation. We also analyzed the effect of ATAD3 and oxidative stress in mtDNA exposure. Our data provide a map of human mtDNA accessibility and demonstrate that nucleoids are dynamically associated with proteins.


Cannabidiol Induces Apoptosis and Perturbs Mitochondrial Function in Human and Canine Glioma Cells.
Cannabidiol (CBD), the major non-psychoactive compound found in cannabis, is frequently used both as a nutraceutical and therapeutic. Despite anecdotal evidence as an anticancer agent, little is known about the effect CBD has on cancer cells. Given the intractability and poor prognoses of brain cancers in human and veterinary medicine, we sought to characterize the in vitro cytotoxicity of CBD on human and canine gliomas. Glioma cells treated with CBD showed a range of cytotoxicity from 4.9 to 8.2 μg/ml; canine cells appeared to be more sensitive than human. Treatment with >5 μg/ml CBD invariably produced large cytosolic vesicles. The mode of cell death was then interrogated using pharmacologic inhibitors. Inhibition of apoptosis was sufficient to rescue CBD-mediated cytotoxicity. Inhibition of RIPK3, a classical necroptosis kinase, also rescued cells from death and prevented the formation of the large cytosolic vesicles. Next, cellular mitochondrial activity in the presence of CBD was assessed and within 2 hours of treatment CBD reduced oxygen consumption in a dose dependent manner with almost complete ablation of activity at 10 μg/ml CBD. Fluorescent imaging with a mitochondrial-specific dye revealed that the large cytosolic vesicles were, in fact, swollen mitochondria. Lastly, calcium channels were pharmacologically inhibited and the effect on cell death was determined. Inhibition of mitochondrial channel VDAC1, but not the TRPV1 channel, rescued cells from CBD-mediated cytotoxicity. These results demonstrate the cytotoxic nature of CBD in human and canine glioma cells and suggest a mechanism of action involving dysregulation of calcium homeostasis and mitochondrial activity.


Efficiency is prioritised over fairness when distributing joint actions.
Individuals have a drive towards maximising action efficiency, which is reflected in action choices that minimise movement costs to reach a goal. In joint actions, actors prioritise joint efficiency or coefficiency, maximising the utility of the joint action even if this comes at a cost to themselves. However, it remains an open question whether actors are willing to unilaterally sacrifice their partner's individual efficiency for the greater good, when forcing a partner to incur additional costs may be interpreted as unfair. In two experiments we explored how participants would choose to distribute a motor task that required either a fair or an unfair distribution of labour. We found that, both whether there was opportunity for reciprocity (Experiment 1) or not (Experiment 2), participants maximised the coefficiency of their joint actions, regardless of how unfair this distribution of labour proved to be regarding the individual action costs. Taken together, our results suggest participants use a rational decision-making framework that prioritises overall efficiency over both individual efficiency and a consideration of fairness.