A randomized controlled pilot study of the University of Minnesota mentoring excellence training academy: A hybrid learning approach to research mentor training.
Research mentor training is a valuable professional development activity. Options for training customization (by delivery mode, dosage, content) are needed to address the many critical attributes of effective mentoring relationships and to support mentors in different institutional settings. We conducted a pilot randomized controlled trial to evaluate a hybrid mentor training approach consisting of an innovative, 90-minute, self-paced, online module (Optimizing the Practice of Mentoring, OPM) followed by workshops based on the Entering Mentoring (EM) curriculum. Mentors (n = 59) were randomized to intervention or control arms; the control condition was receipt of a two-page mentoring tip sheet. Surveys (pre, post, 3-month follow up) and focus groups assessed training impact (self-appraised knowledge, skills, behavior change) and participants' perceptions of the blended training model. The intervention (∼6.5 hours) produced significant improvements in all outcomes, including skills gains on par with those reported previously for the 8-hour EM model. Knowledge gains and intention-to-change mentoring practices were realized after completion of OPM and augmented by the in-person sessions. Mentors valued the synergy of the blended learning format, noting the unique strengths of each modality and specific benefits to completing a foundational online module before in-person engagement. Findings from this pilot trial support the value of e-learning approaches, both as standalone curricula or as a component of hybrid implementation models, for the professional development of research mentors.


Genome organization of more than 300 defensin-like genes in Arabidopsis.
Defensins represent an ancient and diverse set of small, cysteine-rich, antimicrobial peptides in mammals, insects, and plants. According to published accounts, most species' genomes contain 15 to 50 defensins. Starting with a set of largely nodule-specific defensin-like sequences (DEFLs) from the model legume Medicago truncatula, we built motif models to search the near-complete Arabidopsis (Arabidopsis thaliana) genome. We identified 317 DEFLs, yet 80% were unannotated at The Arabidopsis Information Resource and had no prior evidence of expression. We demonstrate that many of these DEFL genes are clustered in the Arabidopsis genome and that individual clusters have evolved from successive rounds of gene duplication and divergent or purifying selection. Sequencing reverse transcription-PCR products from five DEFL clusters confirmed our gene predictions and verified expression. For four of the largest clusters of DEFLs, we present the first evidence of expression, most frequently in floral tissues. To determine the abundance of DEFLs in other plant families, we used our motif models to search The Institute for Genomic Research's gene indices and identified approximately 1,100 DEFLs. These expressed DEFLs were found mostly in reproductive tissues, consistent with our reverse transcription-PCR results. Sequence-based clustering of all identified DEFLs revealed separate tissue- or taxon-specific subgroups. Previously, we and others showed that more than 300 DEFL genes were expressed in M. truncatula nodules, organs not present in most plants. We have used this information to annotate the Arabidopsis genome and now provide evidence of a large DEFL superfamily present in expressed tissues of all sequenced plants.


Radiation exposure associated with percutaneous fluoroscopically guided lag screw fixation for sacroiliac luxation in dogs.
To determine radiation exposure to surgical personnel and to evaluate the accuracy of a modified percutaneous lag screw fixation technique for sacroiliac luxation (SIL) under fluoroscopic guidance in dogs. Cadaveric experimental study. Seventeen beagle cadavers with iatrogenic SIL. Seventeen beagles with iatrogenic SIL underwent reduction and stabilization with 3.5-mm screws. Hypodermic needles (14 gauge) and fluoroscopy were used to orient two Kirschner wires for temporary stabilization and to guide drilling of glide and pilot holes using cannulated drill bits. Duration of surgery and radiation exposure were recorded. Postoperative computed tomographic evaluation of screw position and angulation was performed. Average time for fixation was 15.85 minutes (range, 6.37-33.5). Cumulative radiation doses of 0.4 mrem for the dominant arm of the assistant and 0 mrem for the primary surgeon were recorded. The mean dorsoventral and craniocaudal screw angles were 0.68° ± 3.4° (range - 5.4° to 9.5°) and 1.9° ± 3.2° (range - 4.3° to 9.1°), respectively. Sixteen of the 17 dogs had 100% sacral screw purchase, with the remaining case achieving 93.4% purchase. Fluoroscopy-assisted percutaneous placement of 3.5-mm cortical screws in lag fashion performed with 14-gauge needles in conjunction with Kirschner wires and cannulated drill bits yielded repeatable accurate screw placement with low levels of ionizing radiation exposure to the surgical team. The described technique may be a viable method for minimally invasive osteosynthesis fixation of SIL with low levels of radiation exposure to the surgical team. These results provide evidence to support further evaluation of radiation exposure in clinical cases and can aid in study design and sample size determination.


Cyclase-associated protein interacts with actin filament barbed ends to promote depolymerization and formin displacement.
Cyclase-associated protein (CAP) has emerged as a central player in cellular actin turnover, but its molecular mechanisms of action are not yet fully understood. Recent studies revealed that the N terminus of CAP interacts with the pointed ends of actin filaments to accelerate depolymerization in conjunction with cofilin. Here, we use in vitro microfluidics-assisted TIRF microscopy to show that the C terminus of CAP promotes depolymerization at the opposite (barbed) ends of actin filaments. In the absence of actin monomers, full-length mouse CAP1 and C-terminal halves of CAP1 (C-CAP1) and CAP2 (C-CAP2) accelerate barbed end depolymerization. Using mutagenesis and structural modeling, we show that these activities are mediated by the WH2 and CARP domains of CAP. In addition, we observe that CAP collaborates with profilin to accelerate barbed end depolymerization and that these effects depend on their direct interaction, providing the first known example of CAP-profilin collaborative effects in regulating actin. In the presence of actin monomers, CAP1 attenuates barbed end growth and promotes formin dissociation. Overall, these findings demonstrate that CAP uses distinct domains and mechanisms to interact with opposite ends of actin filaments and drive turnover. Further, they contribute to the emerging view of actin barbed ends as sites of dynamic molecular regulation, where numerous proteins compete and cooperate with each other to tune polymer dynamics, similar to the rich complexity seen at microtubule ends.


Alpha-Synuclein, a Novel Viral Restriction Factor Hiding in Plain Sight.
Alpha-synuclein (α-syn) is a highly conserved protein encoded by the SNCA gene and is expressed uniquely in neurons of both the central and peripheral nervous systems (CNS and PNS). α-Syn is known to cause sporadic and familial forms of Parkinson's disease (PD). However, the role for neuronal expression of α-syn in the first place remains unknown. We review and discuss recently published work that suggests a novel role for α-syn expression in neurons as a restriction factor that inhibits virus transmission from the PNS to the CNS. The potential new role for α-syn expression as a virus inhibitor may provide new approaches to understand the pathogenesis of PD and provide novel approaches to prevent and treat this common neurodegenerative disease.


Serial Stimulation of Invariant Natural Killer T Cells with Covalently Stabilized Bispecific T-cell Engagers Generates Antitumor Immunity While Avoiding Anergy.
CD1d-restricted invariant natural killer T cells (iNKT cells) mediate strong antitumor immunity when stimulated by glycolipid agonists. However, attempts to develop effective iNKT cell agonists for clinical applications have been thwarted by potential problems with dose-limiting toxicity and by activation-induced iNKT cell anergy, which limits the efficacy of repeated administration. To overcome these issues, we developed a unique bispecific T-cell engager (BiTE) based on covalent conjugates of soluble CD1d with photoreactive analogues of the glycolipid α-galactosylceramide. Here we characterize the in vivo activities of iNKT cell-specific BiTEs and assess their efficacy for cancer immunotherapy in mouse models using transplantable colorectal cancer or melanoma tumor lines engineered to express human Her2 as a tumor-associated antigen. Systemic administration of conjugated BiTEs stimulated multiple iNKT cell effector functions including cytokine release, secondary activation of NK cells, and induction of dendritic cell maturation and also initiated epitope spreading for tumor-specific CD8+ cytolytic T-cell responses. The antitumor effects of iNKT-cell activation with conjugated BiTEs were further enhanced by simultaneous checkpoint blockade with antibodies to CTLA-4, providing a potential approach for combination immunotherapy. Multiple injections of covalently stabilized iNKT cell-specific BiTEs activated iNKT cells without causing iNKT cell anergy or exhaustion, thus enabling repeated administration for effective and nontoxic cancer immunotherapy regimens. SIGNIFICANCE: Covalently stabilized conjugates that engage the antigen receptors of iNKT cells and target a tumor antigen activate potent antitumor immunity without induction of anergy or depletion of the responding iNKT cells.


Augmenting one-session treatment of children's specific phobias with attention training to positive stimuli.
This study examined the efficacy of combining two promising approaches to treating children's specific phobias, namely attention training and one 3-h session of exposure therapy ('one-session treatment', OST). Attention training towards positive stimuli (ATP) and OST (ATP+OST) was expected to have more positive effects on implicit and explicit cognitive mechanisms and clinical outcome measures than an attention training control (ATC) condition plus OST (ATC+OST). Thirty-seven children (6-17 years) with a specific phobia were randomly assigned to ATP+OST or ATC+OST. In ATP+OST, children completed 160 trials of attention training responding to a probe that always followed the happy face in happy-angry face pairs. In ATC+OST, the probe appeared equally often after angry and happy faces. In the same session, children completed OST targeting their phobic situation/object. Clinical outcomes included clinician, parent and child report measures. Cognitive outcomes were assessed in terms of change in attention bias to happy and angry faces and in danger and coping expectancies. Assessments were completed before and after treatment and three-months later. Compared to ATC+OST, the ATP+OST condition produced (a) significantly greater reductions in children's danger expectancies about their feared situations/object during the OST and at three-month follow-up, and (b) significantly improved attention bias towards positive stimuli at post-treatment, which in turn, predicted a lower level of clinician-rated phobia diagnostic severity three-months after treatment. There were no significant differences between ATP+OST and ATC+OST conditions in clinician, parent, or child-rated clinical outcomes. Training children with phobias to focus on positive stimuli is effective in increasing attention towards positive stimuli and reducing danger expectancy biases. Studies with larger sample sizes and a stronger 'dose' of ATP prior to the OST may reveal promising outcomes on clinical measures for training attention towards positive stimuli.


Can Sleep Quality Attributes be Predicted from Physical Activity in Everyday Settings?
Sleep is crucial for physical, mental, and emotional well-being. Physical activity and sleep are known to be interrelated; however, limited research has been performed to investigate their interactions in long-term. Conventional studies have presented sleep quality prediction, focusing on a single sleep quality aspect, such as sleep efficiency. In addition, the relationship between daily physical activity and sleep quality has yet to be explored, despite physical activities being utilized in previous studies for sleep quality prediction. In this paper, we develop an Extreme Gradient boosting method to predict sleep duration, sleep efficiency, and deep sleep based on users' daily activity information collected from wearable devices. Our model is trained and tested using data collected with an OURA ring from 34 pregnant mothers for six months under free-living conditions. Our finding shows an accuracy of 90.58%, 95.38%, and 91.45% for sleep duration, efficiency, and deep sleep, respectively. Moreover, we assess the contribution of each physical activity parameter to the prediction results using the Shapley Additive Explanations method. Our results indicate that sedentary time is the most influential parameter for sleep duration prediction, while the inactive time feature (e.g., resting or lying down) has a strong negative relationship with sleep efficiency, and the pregnancy week is the most critical parameter for deep sleep prediction.


[Cutaneous coagulase-negative staphylococci--always harmless?].
Staphylococcus lugdunensis belongs to the group of coagulase-negative staphylococci, but share many clinical and microbiological characteristics with Staphylococcus aureus. We report two cases of chronic recurrent purulent skin infections in two females (one immunocompetent, the other HIV-infected with CD4 cell counts of 438/microl) who were treated repeatedly with antibiotic and surgical interventions, but only became free of recurrences after this was combined with a decontamination strategy.


Roles of Proximate Determinants of Fertility in Recent Fertility Decline in Ethiopia: Application of the Revised Bongaarts Model.
In Ethiopia, the fertility rate declined from 5.4 in 2005 to 4.6 by 2016. Many factors have been contributing to this decline. Understanding the factors contributing to the fertility decline and their level of fertility inhibiting effect has a paramount policy implication in any country. This study aimed to assess the contribution of the four proximate determinants of fertility, ie, contraception use, postpartum infecundity, marriage and abortion rate, to fertility decline in Ethiopia since 2005. This study used publicly available data from the Ethiopia Demographic and Health Surveys (EDHS) of 2005, 2011 and 2016. The EDHS data were the representative data collected from the reproductive-age women through a cross-sectional study. The revised and fine-tuned Bongaarts model of proximate fertility determinants was used for data analysis. The components needed for the analysis were extracted from the full EDHS data using the STAT compiler. Finally, the analysis was done using Microsoft Excel. Of the four proximate determinants of fertility, postpartum insusceptibility contributed the highest fertility inhibiting effect in all three EDHS, and its level was also more prominent among the poorest women. While post partum infecundity, marriage and abortion had a relatively constant effect on fertility over the last 15 years, the fertility inhibiting effect of contraceptive use significantly increased from 15% to 37%. In conclusion, fertility variation in Ethiopia is largely due to the three intermediate determinants of fertility. Over the last one and half decades, contraceptive use was the single most important determinant responsible for fertility decline in Ethiopia. To achieve fertility at replacement level, the country needs a contraceptive prevalence rate of 69%, an increment of nearly 100% from its current contraceptive prevalence rate.


Approaches to Predicting Outcomes in Patients with Acute Kidney Injury.
Despite recognition that Acute Kidney Injury (AKI) leads to substantial increases in morbidity, mortality, and length of stay, accurate prognostication of these clinical events remains difficult. It remains unclear which approaches to variable selection and model building are most robust. We used data from a randomized trial of AKI alerting to develop time-updated prognostic models using stepwise regression compared to more advanced variable selection techniques. We randomly split data into training and validation cohorts. Outcomes of interest were death within 7 days, dialysis within 7 days, and length of stay. Data elements eligible for model-building included lab values, medications and dosages, procedures, and demographics. We assessed model discrimination using the area under the receiver operator characteristic curve and r-squared values. 2241 individuals were available for analysis. Both modeling techniques created viable models with very good discrimination ability, with AUCs exceeding 0.85 for dialysis and 0.8 for death prediction. Model performance was similar across model building strategies, though the strategy employing more advanced variable selection was more parsimonious. Very good to excellent prediction of outcome events is feasible in patients with AKI. More advanced techniques may lead to more parsimonious models, which may facilitate adoption in other settings.


Gastrointestinal tract symptoms among persons with diabetes mellitus in the community.
Gastrointestinal (GI) tract symptoms are common among patients with diabetes mellitus (DM) seen in tertiary care centers. The degree to which this reflects referral bias is unclear. To determine whether GI tract symptoms are more prevalent in unselected patients with DM from the general community compared with their age- and sex-matched counterparts without DM and to assess the association of GI tract symptoms in persons with DM with psychosomatic symptoms, medication use, and symptoms of autonomic neuropathy. In this population-based, cross-sectional study, Olmsted County, Minnesota, residents with type 1 DM, a random sample of residents with type 2 DM, and 2 age- and sex-stratified random samples of nondiabetic residents (total of 1262 person for the 4 groups) were mailed a previously validated symptom questionnaire. Heartburn was less common in residents with type 1 DM vs controls (12% vs 23%; P<.05). No significant difference in prevalence was detected (residents with type 1 DM vs controls; residents with type 2 DM vs controls) for nausea or vomiting (12% vs 11%; 6% vs 6%), dyspepsia (19% vs 21%; 13% vs 17%), or constipation (17% vs 14%; 10% vs 12%). However, constipation and/or laxative use was slightly more common in residents with type 1 DM (27% vs 19%; P<.15), particularly in men, and was associated with the intake of calcium channel blockers. In the community, the prevalence of most GI tract symptoms is similar in persons with or without DM, except for a lower prevalence of heartburn and an increased prevalence of constipation or laxative use in residents with type 1 DM, especially in men. This difference is associated with calcium channel blocker use rather than symptoms of autonomic neuropathy. In community-based practices, physicians should not immediately assume that GI tract symptoms in patients with DM represent a complication of DM.


Prospective evaluation of a two-tiered trauma activation protocol in an Australian major trauma referral hospital.
To evaluate a two-tiered trauma activation protocol in a major trauma referral hospital in Australia. A prospective study performed over a 12-month period of all consecutive trauma activations in a major trauma referral hospital. The triage tool assigned patients into two tiers of trauma activation. The full trauma activation was initiated where physiological or anatomical criteria were present. These patients were assessed by a multispecialty trauma team. A consult trauma activation was initiated where only mechanism of injury criteria was present. These patients were assessed by the Emergency Department Registrar and Surgical Registrar. The primary endpoint was major trauma outcome defined as either injury severity score (ISS) greater than 15, requirement for High Dependency Unit or Intensive Care Unit (HDU/ICU) admission, need for urgent operative intervention, or in hospital mortality. Of 1144 trauma activations, 468 (41%) were full trauma and 676 (59%) were consult trauma activations. The full trauma activation group had a significantly higher proportion of the major trauma outcome (34% vs. 5%, p<0.01) and all 18 patients (2%) who died were in the full trauma activation group. Sensitivity of the triage tool for the major trauma outcome was 83%, specificity was 68%, undertriage was 3% and overtriage was 27%. The two-tiered trauma activation protocol is effective in identifying patients with major trauma from those with minor trauma. There were no deaths in undertriaged patients.


Coconut Oil Aggravates Pressure Overload-Induced Cardiomyopathy without Inducing Obesity, Systemic Insulin Resistance, or Cardiac Steatosis.
Studies evaluating the effects of high-saturated fat diets on cardiac function are most often confounded by diet-induced obesity and by systemic insulin resistance. We evaluated whether coconut oil, containing C12:0 and C14:0 as main fatty acids, aggravates pressure overload-induced cardiomyopathy induced by transverse aortic constriction (TAC) in C57BL/6 mice. Mortality rate after TAC was higher (p < 0.05) in 0.2% cholesterol 10% coconut oil diet-fed mice than in standard chow-fed mice (hazard ratio 2.32, 95% confidence interval 1.16 to 4.64) during eight weeks of follow-up. The effects of coconut oil on cardiac remodeling occurred in the absence of weight gain and of systemic insulin resistance. Wet lung weight was 1.76-fold (p < 0.01) higher in coconut oil mice than in standard chow mice. Myocardial capillary density (p < 0.001) was decreased, interstitial fibrosis was 1.88-fold (p < 0.001) higher, and systolic and diastolic function was worse in coconut oil mice than in standard chow mice. Myocardial glucose uptake was 1.86-fold (p < 0.001) higher in coconut oil mice and was accompanied by higher myocardial pyruvate dehydrogenase levels and higher acetyl-CoA carboxylase levels. The coconut oil diet increased oxidative stress. Myocardial triglycerides and free fatty acids were lower (p < 0.05) in coconut oil mice. In conclusion, coconut oil aggravates pressure overload-induced cardiomyopathy.


Effects of inspiratory muscle training on dynamic hyperinflation in patients with COPD.
Dynamic hyperinflation has important clinical consequences in patients with chronic obstructive pulmonary disease (COPD). Given that most of these patients have respiratory and peripheral muscle weakness, dyspnea and functional exercise capacity may improve as a result of inspiratory muscle training (IMT). The aim of the study was to analyze the effects of IMT on exercise capacity, dyspnea, and inspiratory fraction (IF) during exercise in patients with COPD. Daily inspiratory muscle strength and endurance training was performed for 8 weeks in 10 patients with COPD GOLD II and III. Ten patients with COPD II and III served as a control group. Maximal inspiratory pressure (Pimax) and endurance time during resistive breathing maneuvers (tlim) served as parameter for inspiratory muscle capacity. Before and after training, the patients performed an incremental symptom limited exercise test to maximum and a constant load test on a cycle ergometer at 75% of the peak work rate obtained in the pretraining incremental test. ET was defined as the duration of loaded pedaling. Following IMT, there was a statistically significant increase in inspiratory muscle performance of the Pimax from 7.75 ± 0.47 to 9.15 ± 0.73 kPa (P < 0.01) and of tlim from 348 ± 54 to 467 ± 58 seconds (P < 0.01). A significant increase in IF, indicating decreased dynamic hyperinflation, was observed during both exercise tests. Further, the ratio of breathing frequency to minute ventilation (bf/V'(E)) decreased significantly, indicating an improved breathing pattern. A significant decrease in perception of dyspnea was also measured. Peak work rate during the incremental cycle ergometer test remained constant, while ET during the constant load test increased significantly from 597.1 ± 80.8 seconds at baseline to 733.6 ± 74.3 seconds (P < 0.01). No significant changes during either exercise tests were measured in the control group. The present study found that in patients with COPD, IMT results in improvement in performance, exercise capacity, sensation of dyspnea, and improvement in the IF prognostic factor.


Analysis of protein dynamics with tandem fluorescent protein timers.
Fluorescent timers (FTs) are fluorescent proteins that change color with time. FTs can be used as tags to follow protein dynamics in living cells. Recently we described a novel class of FTs called tandem fluorescent protein timers (tFTs). Each tFT is a tandem fusion of two different conventional fluorescent proteins having distinct kinetics of fluorophore maturation. tFTs suitable for studying protein dynamics on different scales can be generated from a broad range of commonly used fluorescent proteins. Here we describe how to establish new tFTs and consider potential pitfalls. We detail a protocol for quantitative fluorescence microscopy imaging and analysis of intracellular protein dynamics with tFTs in the budding yeast Saccharomyces cerevisiae.


Pathogenesis, detection, and control of scrapie in sheep.
In sheep, scrapie is a fatal neurologic disease that is caused by a misfolded protein called a prion (designated PrPSc). The normal cellular prion protein (PrPC) is encoded by an endogenous gene, PRNP, that is present in high concentrations within the CNS. Although a broad range of functions has been described for PrPC, its entire range of functions has yet to be fully elucidated. Accumulation of PrPSc results in neurodegeneration. The PRNP gene has several naturally occurring polymorphisms, and there is a strong correlation between scrapie susceptibility and PRNP genotype. The cornerstone of scrapie eradication programs is the selection of scrapie-resistant genotypes to eliminate classical scrapie. Transmission of classical scrapie in sheep occurs during the prenatal and periparturient periods when lambs are highly susceptible. Initially, the scrapie agent is disseminated throughout the lymphoid system and into the CNS. Shedding of the scrapie agent occurs before the onset of clinical signs. In contrast to classical scrapie, atypical scrapie is believed to be a spontaneous disease that occurs in isolated instances in older animals within a flock. The agent that causes atypical scrapie is not considered to be naturally transmissible. Transmission of the scrapie agent to species other than sheep, including deer, has been experimentally demonstrated as has the transmission of nonscrapie prion agents to sheep. The purpose of this review is to outline the current methods for diagnosing scrapie in sheep and the techniques used for studying the pathogenesis and host range of the scrapie agent. Also discussed is the US scrapie eradication program including recent updates.


Hydrogenase activity in Rhodopseudomonas capsulata: relationship with nitrogenase activity.
Hydrogenase activity was found in cells of Rhodopseudomonas capsulata strain B10 cultured under a variety of growth conditions either anaerobically in the light or aerobically in the dark. The highest activities were found routinely in cells grown in the presence of H2. The hydrogenase of R. capsulata was localized in the particulate fraction of the cells. High hydrogenase activities were usually observed in cells possessing an active nitrogenase. The hydrogen produced by the nitrogenase stimulated the activity of hydrogenase in growing cells. However, the synthesis of hydrogenase was not closely linked to the synthesis of nitrogenase. Hydrogenase was present in dark-grown cultures, whereas nitrogenase synthesis was not significant in the absence of light. Unlike nitrogenase, hydrogenase was present in cultures grown on NH4+. Conditions were established which allowed the synthesis of either nitrogenase or hydrogenase by resting cells. We concluded that hydrogenase can be synthesized independently of nitrogenase.


CCCTC-binding factor recruitment to the early region of the human papillomavirus 18 genome regulates viral oncogene expression.
Host cell differentiation-dependent regulation of human papillomavirus (HPV) gene expression is required for productive infection. The host cell CCCTC-binding factor (CTCF) functions in genome-wide chromatin organization and gene regulation. We have identified a conserved CTCF binding site in the E2 open reading frame of high-risk HPV types. Using organotypic raft cultures of primary human keratinocytes containing high-risk HPV18 genomes, we show that CTCF recruitment to this conserved site regulates viral gene expression in differentiating epithelia. Mutation of the CTCF binding site increases the expression of the viral oncoproteins E6 and E7 and promotes host cell proliferation. Loss of CTCF binding results in a reduction of a specific alternatively spliced transcript expressed from the early gene region concomitant with an increase in the abundance of unspliced early transcripts. We conclude that high-risk HPV types have evolved to recruit CTCF to the early gene region to control the balance and complexity of splicing events that regulate viral oncoprotein expression. The establishment and maintenance of HPV infection in undifferentiated basal cells of the squamous epithelia requires the activation of a subset of viral genes, termed early genes. The differentiation of infected cells initiates the expression of the late viral transcripts, allowing completion of the virus life cycle. This tightly controlled balance of differentiation-dependent viral gene expression allows the virus to stimulate cellular proliferation to support viral genome replication with minimal activation of the host immune response, promoting virus productivity. Alternative splicing of viral mRNAs further increases the complexity of viral gene expression. In this study, we show that the essential host cell protein CTCF, which functions in genome-wide chromatin organization and gene regulation, is recruited to the HPV genome and plays an essential role in the regulation of early viral gene expression and transcript processing. These data highlight a novel virus-host interaction important for HPV pathogenicity.


Toxoplasma gondii infection enhances the kairomonal valence of rat urine.
Many animals use chemicals as pheromones to communicate between individuals of the same species, for example to influence mate choice or to assert dominance. Pheromonal communication is an open broadcast system that can be intercepted by unintended receivers such as predators and prey. We have recently reported that male rats infected by the protozoan parasite Toxoplasma gondii become more attractive to female rats. This suggests a facilitatory effect of infection on rat pheromone production. In view of the open nature of pheromonal communication, we postulate that Toxoplasma gondii infection collateraly enhances kairomonal valence of infected rats to their prey. We compared the strength of kairomonal interception by mice when using scent marks from rats infected with Toxoplasma gondii vs. marks from uninfected control rats. Mice exhibited greater avoidance to both fresh urine and aged rat urine marks obtained from infected animals. These results indicate that, at least in some cases, parasitism can result in opportunity costs for hosts by making prey species more averse to them.


Ghrelin modulates dopaminergic neuron formation and attention deficit hyperactivity disorder-like behaviors: From animals to human models.
Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent psychiatric disorders in children. The orexigenic hormone ghrelin is important in neuroprotection and neurodevelopment, which may play an important role in psychopathogenesis of ADHD. This study aimed to systematically investigate the genomic and pharmacological manipulations of ghrelin functioning in ADHD-like symptoms in zebrafish models and validated the effects of ghrelin polymorphisms in human subjects with ADHD. We firstly generated ghrelinΔ/Δ zebrafish mutant, which displayed hyperactive, attention deficit-like and impulsive-like behaviors, as well as endophenotypes, mimicking human ADHD. GhrelinΔ/Δ zebrafish exhibited downregulated expression levels of wnt1, wnt3a, wnt5a that are critical for dopaminergic neuron development to possibly regulate their number and spatial organization. Pharmacological blockade of wnt signaling with XAV939 induced a reduced moving activity and less dopaminergic neurons; whereas, wnt agonist SB415286 rescued hyperactivity and dopaminergic neuron loss in ghrelinΔ/Δ zebrafish. In addition, we further identified and validated a SNP, rs696217, on orexigenic hormone preproghrelin/ghrelin (T408T, Met72Met) to be associated with a higher risk of ADHD in a case-controlled association study with 248 subjects with ADHD and 208 subjects of healthy controls. Together, our results reveal a novel endogenous role for orexigenic hormone ghrelin in ADHD, which provides insights into genetic regulation and drug screens for the identification of novel treatments of ADHD.


A pH-Mediated Highly Selective System Enabling Simultaneous Analysis of Circulating RNAs Carried by Extracellular Vesicles and Lipoproteins.
Extracellular vesicles (EVs) and lipoproteins (LPPs) serve as important carriers of circulating miRNAs in peripheral blood, offering immense potential for disease diagnosis and therapeutic interventions. Due to their shared physicochemical attributes, EVs and LPPs are frequently coisolated, potentially leading to misunderstandings regarding their distinct functional roles in physiological and pathological processes. Here, we report a highly selective magnetic system based on the pH-mediated affinity displayed by cibacron blue (CB) toward EVs and LPPs, enabling successful separation and collection of these two nanoparticles without cross-contamination for subsequent circulating RNA analysis. First, we found that CB-modified magnetic beads (CBMBs) exhibit a strong affinity toward LPP particles while displaying little interaction with EVs in standard samples under physiological pH conditions. We further demonstrate that the affinity between CB molecules and bionanoparticles in plasma samples is highly pH-dependent. Specifically, CBMBs show affinities for both LPP and EV particles under neutral and acidic conditions. However, at basic pH levels, CB molecules selectively bind only to LPP particles. Consequently, the remaining EV particles present in plasma are subsequently isolated by using titanium dioxide-modified beads (TiMBs) through phospholipid affinity. The simultaneous analysis of the transcriptomic contents of EV and LPP reveals clear differences in their small RNA profiles, with the differentially expressed RNAs reflecting distinct biological processes. Significantly, in a proof-of-concept study, we successfully demonstrated a strong correlation between miRNAs carried by both EV and LPP particles with the occurrence of ocular neovascularization during the progression of diabetic retinopathy. The involved miRNAs may serve as potential biomarkers for DR diagnostics and severity classification. To sum up, this pH-mediated separation system is not only user-friendly but also highly compatible, rendering it a potent tool for probing the molecular compositions, biomarkers, and underlying biological mechanisms of EVs and LPPs.


A bibliometric analysis of COVID-19 research in Africa.
The COVID-19 pandemic has led to an unprecedented global research effort to build a body of knowledge that can inform mitigation strategies. We carried out a bibliometric analysis to describe the COVID-19 research output in Africa in terms of setting, study design, research themes and author affiliation. We searched for articles published between 1 December 2019 and 3 January 2021 from various databases including PubMed, African Journals Online, medRxiv, Collabovid, the WHO global research database and Google. All article types and study design were included. A total of 1296 articles were retrieved. 46.6% were primary research articles, 48.6% were editorial-type articles while 4.6% were secondary research articles. 20.3% articles used the entire continent of Africa as their study setting while South Africa (15.4%) was the most common country-focused setting. The most common research topics include 'country preparedness and response' (24.9%) and 'the direct and indirect health impacts of the pandemic' (21.6%). However, only 1.0% of articles focus on therapeutics and vaccines. 90.3% of the articles had at least one African researcher as author, 78.5% had an African researcher as first author, while 63.5% had an African researcher as last author. The University of Cape Town leads with the greatest number of first and last authors. 13% of the articles were published in medRxiv and of the studies that declared funding, the Wellcome Trust was the top funding body. This study highlights Africa's COVID-19 research and the continent's existing capacity to carry out research that addresses local problems. However, more studies focused on vaccines and therapeutics are needed to inform local development. In addition, the uneven distribution of research productivity among African countries emphasises the need for increased investment where needed.


Sox9, a novel pancreatic marker in Xenopus.
The pancreas is a mixed exocrine and endocrine gland involved in the control of many homeostatic functions. During embryogenesis, the pancreas arises from dorsal and ventral evaginations of the foregut that will subsequently fuse into a single organ. The characterization of early genes expressed in the developing pancreas is critical to understand its specification and differentiation. Here we report the expression pattern of Sox9, a member of the Sox family of transcription factors, during development of the Xenopus pancreas and compare its expression to that of a well characterized pancreatic marker, Pdx1. By whole-mount in situ hybridization, Sox9 was first detected at stage 25 in the pancreatic anlagen--dorsally in the prospective foregut and ventrally on each side of the liver diverticulum. As development proceeds, Sox9 expression can be used to trace the development of the dorsal and ventral pancreatic buds and their repositioning associated with the dynamic movements of the gastrointestinal tract. Sox9 expression in the pancreatic rudiment was identical to that of Pdx1. However, while Pdx1 is expressed in both the pancreatic buds and the duodenum, Sox9 was restricted to ventral and dorsal pancreatic buds. Sox9 and Pdx1 are thus two of the earliest genes expressed in the presumptive pancreatic tissue.


Influence of Hemodialysis Catheter Insertion on Hemodynamics in the Central Veins.
Central venous catheter (CVC) related thrombosis is a major cause of CVC dysfunction in patients under hemodialysis. The aim of our study was to investigate the impact of CVC insertion on hemodynamics in the central veins and to examine the changes in hemodynamic environments that may be related to thrombus formation due to the implantation of CVC. Patient-specific models of the central veins with and without CVC were reconstructed based on computed tomography images. Flow patterns in the veins were numerically simulated to obtain hemodynamic parameters such as time-averaged wall shear stress (TAWSS), oscillating shear index (OSI), relative residence time (RRT), and normalized transverse wall shear stress (transWSS) under pulsatile flow. The non-Newtonian effects of blood flow were also analyzed using the Casson model. The insertion of CVC caused significant changes in the hemodynamic environment in the central veins. A greater disturbance and increase of velocity were observed in the central veins after the insertion of CVC. As a result, TAWSS and transWSS were markedly increased, but most parts of OSI and RRT decreased. Newtonian assumption of blood flow would overestimate the increase in TAWSS after CVC insertion. High wall shear stress (WSS) and flow disturbance, especially the multidirectionality of the flow, induced by the CVC may be a key factor in initiating thrombosis after CVC insertion. Accordingly, approaches to decrease the flow disturbance during CVC insertion may help restrain the occurrence of thrombosis. More case studies with pre-operative and postoperative modeling and clinical follow-up need to be performed to verify these findings. Non-Newtonian blood flow assumption is recommended in computational fluid dynamics (CFD) simulations of veins with CVCs.


Spontaneous hypnosis in the forensic context.
"Hypnosis" denotes either specific phenomena (altered volition, perception, cognition, and recall) or interpersonal transactions that often elicit them. Basic research leads to paradox: hypnosis is validated, and shown to be dissociative in essence, at the same time that neither its phenomena nor transactions can be separated from those of everyday living without logical absurdity. This paradox can be resolved by assuming that consciousness and volition are complex, occurring simultaneously at many levels in the same waking individual. Hypnotic-like phenomena and transactions occur spontaneously, in either covert or overt forms. The former are pervasive, whereas the latter are often associated with psychological trauma. Forensic implications are twofold: for criminal responsibility, and the reliability of eyewitness testimony. Hypnotic-like states and transactions are rarely affirmed as an insanity defense because at some level these subjects are aware of what they are doing and why. Diminished capacity and mitigation of sentence are more appropriate defense strategies. Several conflicted traditions of case law have evolved to protect eyewitness testimony from hypnotic-like distortions in cognition, perception, and memory that can occur either during or outside of formal hypnotic procedures. These include the admissibility of posthypnotic testimony, due process safeguards at eyewitness identification procedures, and the admissibility of expert testimony on the findings of eyewitness research. These areas are inseparable from one another and demand a systematic coordinated approach.


Why cyclin Y? A highly conserved cyclin with essential functions.
Cyclin Y is one of the most highly conserved members of the cyclin superfamily of proteins, which are famous for their crucial roles in regulating the cell cycle and transcription. Despite this high degree of conservation, very little was known about Cyclin Y function prior to a handful of studies published in this past year. Cyclins typically function by activating cyclin-dependent kinases (Cdks) and one insight has come from the identification of a Cdk that is activated by Cyclin Y. Yeast two-hybrid data first linked Cyclin Y with Cdk14, known as Eip63E in Drosophila or PFTAIRE1 in vertebrates. In Drosophila, both Cyclin Y and Eip63E are essential at many stages of development, from embryogenesis to metamorphosis and null mutants show a similar spectrum of developmental defects. In cultured cells, Cyclin Y and Eip63E were shown to phosphorylate the Wg/Wnt co-receptor Arrow/LRP6 in a ligand-independent manner. Eip63E is recruited to LRP6 at the plasma membrane by interacting with Cyclin Y, which is tethered to the membrane through an N-terminal myristoylation. Cyclin Y-dependent LRP6 phosphorylation appears to prime the receptor for subsequent ligand-dependent phosphorylation and activation of the canonical Wnt signaling pathway. Interestingly, Wnt receptor phosphorylation and signaling is maximal in G₂/M when Cyclin Y is at its highest levels, suggesting that Cyclin Y may serve to entrain Wnt signaling to the cell cycle. Given the wide range of roles for Wnt signaling during development, these studies may help explain why Cyclin Y is required at several developmental stages and in turn why these proteins are so well conserved in metazoans.


Ribosomal Protein RPL27a Promotes Female Gametophyte Development in a Dose-Dependent Manner.
Ribosomal protein mutations in Arabidopsis (Arabidopsis thaliana) result in a range of specific developmental phenotypes. Why ribosomal protein mutants have specific phenotypes is not fully known, but such defects potentially result from ribosome insufficiency, ribosome heterogeneity, or extraribosomal functions of ribosomal proteins. Here, we report that ovule development is sensitive to the level of Ribosomal Protein L27a (RPL27a) and is disrupted by mutations in the two paralogs RPL27aC and RPL27aB. Mutations in RPL27aC result in high levels of female sterility, whereas mutations in RPL27aB have a significant but lesser effect on fertility. Progressive reduction in RPL27a function results in increasing sterility, indicating a dose-dependent relationship between RPL27a and female fertility. RPL27a levels in both the sporophyte and gametophyte affect female gametogenesis, with different developmental outcomes determined by the dose of RPL27a. These results demonstrate that RPL27aC and RPL27aB act redundantly and reveal a function for RPL27a in coordinating complex interactions between sporophyte and gametophyte during ovule development.


[Approach to coronary artery disease in the elderly].
Cardiovascular disease (CVD) is the most important contributor to overall mortality in the general population. More than half of all patients dying from CVD are older than 70 years. Prevention, diagnosis and management of coronary artery disease (CAD) in the elderly population differ in many respects compared to younger patients. Age per se can contribute significantly to overall global cardiovascular risk in the elderly population: in such cases when age is the sole risk factor for CVD, threshold for initiation of pharmacological intervention should be gauged carefully to balance possible side effects and clinical benefits. The use of non-invasive stress test for the diagnosis of CAD is limited by factors like co-morbidities, diminished exercise capacity, and false negative results due to high disease prevalence. While carefully considering possible drug side effects, one should not refrain from optimal medical therapy as recommended by evidence based guidelines in the elderly CAD patients. Biological age, rather than the calendar age, as well as frailty status should be considered while planning treatment in elderly CAD patients: involvement of the patient in the decision process would be beneficial while optimizing the treatment to attain the best risk/benefit ratio in geriatric CAD subjects.


Impacts of Oreochromis mossambicus (Perciformes: Cichlidae) upon habitat segregation among cyprinodontids (Cyprinodontiformes) of a species flock in Mexico.
Five species of Cyprinodon in Laguna Chichancanab, Yucatan, Mexico comprise a young species flock whose ecology and evolution has not been thoroughly studied, but whose existence is threatened with extinction. Species flocks evolve in isolated areas where predators and competitors are absent. Since the description of the Chichancanab flock, Oreochromis mossambicus, a species introduced into the lake for which I examined habitat in the 1980's, has become common throughout the basin. I assessed relative abundance of flock species in the lake. examined habitat use and segregation among the three most common flock species and examined the affects of O. mossambicus upon flock species habitat use. Cyprinodon beltrani was the most abundant flock species in 1997, followed by C. maya and C. labiosus; C. verecundus and C. simus were rare. Cyprinodon beltrani was found in shallow water, nearshore, over thick beds of submerged Chara, and little emergent vegetation. Cyprinodon beltrani exhibited diurnal variation in nearshore habitat use. In the field, the habitat use of C. beltrani and O. mossambicus broadly overlapped. In aquarium experiments, three flock species exhibited habitat use segregation and C. beltrani and C. labiosus showed agonistic behaviors that strengthened segregation. Cyprinodon maya differed from C. beltrani and C. labiosus by its greater dispersion of individuals and use of areas higher in the water column. The presence of O. mossambicus caused a shift in habitat use by C. maya and C. labiosus that put these species into habitat occupied by C. beltrani. The presence of introduced species has caused a significant perturbation of the conditions that fomented speciation of the Chichancanab flock 8,000 years ago.


[Colorectal cancer before 45 years of age].
Colo-rectal cancer in young patients is a subject of interest for many reasons. Various studies are devoted to this subject but controversies regarding the stages, the evolution and the prognosis still remains. We present intermediate results, of an ongoing study, which is directed to those particular aspects of colon cancer of the patients less than 45 years of age in a region where the global incidence of the disease is one of the highest in the world. In the past five years, we have observed 602 patients with colon cancer. 23 of them (4%) were less than 45 years old. The age at diagnosis was 38 +/- 6 years. Two-thirds of the subjects were male. 13% had had predisposing conditions for colon cancer such as FAP, ulcerative colitis or Turcot syndrome; 50% had a positive familial history for cancer. Symptoms lasted for less than 3 months in two thirds of the patients. 15% had a right sided tumor, 38% were located in the sigmoid and 28.5% in the rectum. At diagnosis, the tumors were classified as follows: 32% Dukes B, 23% Dukes C and 40% were disseminated disease. Most of them were located in the rectum, but 43% of Dukes B lesions were located in ascending or transverse colon. Grading reveal moderately to poorly differentiated tumors in 3/4 of cases. 30% of patients received an adjuvant therapy. After two years, 70% of the patients were alive. None of them with Dukes A or B but one of the patients with Dukes C were dead.(ABSTRACT TRUNCATED AT 250 WORDS)


Woodwind instrument design optimization based on impedance characteristics with geometric constraints.
Computational optimization algorithms coupled with acoustic models of wind instruments provide instrument makers with an opportunity to explore new designs. Specifically, they enable the automatic discovery of geometries exhibiting desired resonance characteristics. In this paper, the design optimization of woodwind instruments with complex geometrical features (e.g., non-cylindrical bore profile and side holes with various radii and chimney heights) is investigated. Optimal geometric designs are searched so that their acoustic input impedance has peaks with specific target frequencies and amplitudes. However, woodwind instruments exhibit complex input impedance whose features, such as resonances, might have non-smooth evolution with respect to design variables, thus hampering gradient-based optimization. For this reason, this paper introduces new formulations of the impedance characteristics (resonance frequencies and amplitudes) using a regularized unwrapped angle of the reflection function. The approach is applied to an illustrative instrument subjected to geometric constraints similar to the ones encountered by manufacturers (a key-less pentatonic clarinet with two-registers). Three optimization problems are considered, demonstrating a strategy to simultaneously adjust several impedance characteristics on all fingerings.


The association between radiographic severity and pre-operative function in patients undergoing primary knee replacement for osteoarthritis.
To determine the association between radiographic osteoarthritis (OA) and pre-operative function in patients undergoing primary knee replacement. Single centre study examining pre-operative outcomes in a consecutive series of 525 patients who underwent primary knee replacement for OA between January 2006 and December 2007. Pre-operative data included: demographics, American Society of Anaesthesiologists (ASA) status and OA in the contralateral knee. The International Knee Society (IKS) rating and Short Form-12 (SF-12) were recorded for each patient. Pre-operative radiographs were read by a single observer for Kellgren and Lawrence (K&L) grading and Osteoarthritis Research Society International (OARSI) atlas features. Multiple linear regression was used to assess the strength of associations between radiographic OA severity and function, adjusting for clinically relevant variables. Lateral tibiofemoral osteophyte grade was an independent predictor of pre-operative function as determined by the functional sub-scale of the IKS in patients undergoing primary knee replacement (coefficient=2.58, p=0.033). No associations were evident between pre-operative function and modified K&L, joint space narrowing, Ahlbäck attrition and coronal plane deformity. Other statistically significant predictors of poorer pre-operative function included: advancing age, female gender, knee pain and poorer SF-12 mental component summary scores which including osteophyte grade accounted for 24.6% of the variation in functional scores, (r=0.496). Osteophytes in the lateral compartment of the knee were associated with pre-operative function in patients with advanced knee OA. Further studies are required which examine individual radiographic features specifically in patients with advanced knee OA to determine their relationship to pre-operative pain and function.


[Psychiatric disorders in patients with Cushing's disease before and after neurosurgery].
Cushing's disease which is a consequence of ACTH-secreting pituitary adenoma leads to hypercortisolism. Cushing's disease is associated with several psychiatric disturbances. The aim of the present study was to identify which psychiatric disorders were present in patients with Cushing's disease over a 2-year period and to monitor their general psychiatric condition. Additionally, the study aimed to examine the relationship between the duration of Cushing's disease, and the severity of psychiatric conditions based on psychiatric rating scales. The study included 39 patients with Cushing's disease that underwent neurosurgery for ACTH-secreting pituitary adenomas. The transsphenoidal approach (the standard microsurgery technique) was performed in all patients. ACTH-secreting pituitary adenomas were confirmed based on immunohistochemistry in all patients. Psychiatric conditions in the patients were identified using the Clinical Global Impression Scale (CGI) and ICD 10 diagnostic criteria at 3 time points: prior to surgery, and 6 and 48 months post surgery. The Cushing's disease patients exhibited statistically significant improvement in their psychiatric condition, according to the CGI, 6 and 48 months post surgery. There wasn't any significant correlation between the duration of Cushing's disease and psychiatric status, as measured by the CGI prior to surgery, 6 months post surgery, or 48 months post surgery. Patients with Cushing's disease had a significant level psychiatric disturbance that remitted after surgery. There wasn't a significant correlation between the duration of Cushing's disease and psychiatric status.


Use of transesophageal echocardiography for postoperative evaluation of right ventricular function.
No method has been available to assess the right ventricular (RV) pressure-volume relation in the operating room or intensive care unit. Left ventricular cross-sectional area measured by echocardiography using the technology of automated border detection has been used to construct left ventricular pressure-area (P-A) loops. In the human right ventricle, however, this approach has not been validated. We recorded RV P-A loops in 14 patients in the intensive care unit using transesophageal echocardiography. Multiple RV P-A loops were obtained by reducing preload with intravenous nitroglycerin, thereby elucidating the end-systolic P-A relation. With an incremental dose of dobutamine, the slope of the RV end-systolic P-A relation increased (from 4.56+/-2.42 to 7.34+/-3.62 mm Hg/cm2, p<0.01), with no change in the x-axis intercept, which implied increased contractility. Furthermore, in the operating room we validated the use of RV cross-sectional area as a surrogate for RV volume by demonstrating the close correlation between the stroke area (maximal RV area minus minimal RV area) and stroke volume (r = 0.962; p<0.0001). Transesophageal echocardiography with automated border detection is a promising tool for elucidating RV function through the analysis of RV P-A loops.


Biological effects of staphylococcal protein A immunotherapy in cats with induced feline leukemia virus infection.
Biological effects of staphylococcal protein A (SPA) immunotherapy were studied in 5 viremic and 6 nonviremic cats with induced FeLV infection and in 6 control cats. The SPA therapy neither reversed FeLV viremia nor resulted in consistent improvement in humoral immune responses to FeLV antigens. However, SPA immunotherapy induced a proliferative response in bone marrow granulocytic lineage, possibly resulting in expression of FeLV-free mature neutrophils in the blood. Seemingly, viral burden and chemiluminescent responses were reversed in viremic cats during SPA immunotherapy.


Role of MXD3 in proliferation of DAOY human medulloblastoma cells.
A subset of medulloblastomas, the most common brain tumor in children, is hypothesized to originate from granule neuron precursors (GNPs) in which the sonic hedgehog (SHH) pathway is over-activated. MXD3, a basic helix-look-helix zipper transcription factor of the MAD family, has been reported to be upregulated during postnatal cerebellar development and to promote GNP proliferation and MYCN expression. Mxd3 is upregulated in mouse models of medulloblastoma as well as in human medulloblastomas. Therefore, we hypothesize that MXD3 plays a role in the cellular events that lead to medulloblastoma biogenesis. In agreement with its proliferative role in GNPs, MXD3 knock-down in DAOY cells resulted in decreased proliferation. Sustained overexpression of MXD3 resulted in decreased cell numbers due to increased apoptosis and cell cycle arrest. Structure-function analysis revealed that the Sin3 interacting domain, the basic domain, and binding to E-boxes are essential for this activity. Microarray-based expression analysis indicated up-regulation of 84 genes and down-regulation of 47 genes. Potential direct MXD3 target genes were identified by ChIP-chip. Our results suggest that MXD3 is necessary for DAOY medulloblastoma cell proliferation. However, increased level and/or duration of MXD3 expression ultimately reduces cell numbers via increased cell death and cell cycle arrest.


Assessing the prevalence and predictors of anemia among pregnant women in India: findings from the India National Family Health Survey 2019-2021.
Anemia is more prevalent in low- and middle-income countries including India. Anemia in pregnancy is associated with increased risk of maternal health problems and adverse birth outcomes. This study estimates the prevalence and associated risk factors of anemia among pregnant women in India. This cross-sectional study is based on secondary data from the India National Family Health Survey-V (NFHS-5) conducted during 2019-2021. We extracted data of 27,317 currently pregnant women to estimate the prevalence and contributory factors associated with anemia using descriptive statistics and logistic regression analysis. The prevalence of anemia among pregnant women in India was 52.2%. Anemia was higher among adolescent women (61.5%), those with no education (59.2%), those belonging to poorest wealth index (61.9%), scheduled tribes (59.3%), and those from the eastern region of India (62.1%). Further, it was more prevalent among women with a habit of smoking, tobacco, or alcohol (63.0%), and women with shorter birth intervals (59.7%). Among Indian states, anemia prevalence was higher in the state of Bihar (63.1%) and the union territory of Ladakh (71.4%). Logistic regression models show that women with no education (aOR = 1.41, 95% CI = 1.27-1.57), belonging to a poorest wealth quintile (aOR = 1.69, 95% CI = 1.51-1.90), and those with a habit of smoking, tobacco, or alcohol (aOR = 1.39, 95% CI = 1.18-1.63) were more anemic than their counterparts. Additionally, women with no education showed a four-times higher risk of severe anemia (aOR = 4.79, 95% CI = 2.75-8.36) than their highly educated counterparts. Anemia affects half of all pregnant women in India. Anemia prevalence is higher among adolescents, illiterate, poor, and tribal communities. Social norm-based interventions and strengthening the community health facilitators should be implemented to reduce the high burden of anemia in India.


Robustness of Optimal Circadian Rhythm Entrainment under Model Perturbation.
The optimal circadian rhythm entrainment problem has been studied based on mathematical models, e.g. the Kronauer model. In this paper, we study the robustness of light-based circadian rhythm entrainment under model parameter perturbations as well as propose a feedback control law to improve the robustness of the entrainment strategy. Our study finds the model parameter whose perturbations affect the entrainment the most. We also find that feedback control reduces the sensivitity of the entrainment process to model parameter perturbations.Clinical relevance- Circadian misalignment has negative impacts on health, such as higher risks of cardiovascular disease and cancer. We present a numerical study of how well optimized circadian rhythm entrainment plans that are derived from a generic mathematical model work on personalized cases.


Cognitive resources moderate the adverse impact of poor perceived neighborhood conditions on self-reported physical activity of older adults.
Poor neighborhood conditions are associated with lower levels of physical activity for older adults but socio-ecological models posit that physical activity depends on both environmental and individual factors. Older adults' ability to overcome environmental barriers to physical activity may partially rely on cognitive resources. However, evidence on the moderating role of these cognitive resources in the associations between environmental barriers and physical activity is still lacking. We analyzed cross-national and longitudinal data on 28,393 adults aged 50 to 96 years as part of the SHARE. Lack of access to services and neighborhood nuisances were used as indicators of poor neighborhood conditions. Delayed recall and verbal fluency were used as indicators of cognitive resources. Confounder-adjusted generalized estimation equations were conducted to test associations between neighborhood conditions and self-reported moderate physical activity, as well as the moderating role of cognitive resources. Results showed that poor neighborhood conditions reduced the odds of engagement in physical activity. Cognitive resources robustly reduced the adverse influence of poor neighborhood conditions on physical activity. Participants with lower cognitive resource scores showed lower odds of engaging in physical activity when neighborhood conditions were poorer, whereas these conditions were not related to this engagement for participants with higher cognitive resource scores. These findings suggest that cognitive resources can temper the detrimental effect of poor neighborhood conditions on physical activity. Public policies should target both individual and environmental factors to tackle the current pandemic of physical inactivity more comprehensively.


[Short-term effect of trabecular metal rod implant on early avascular necrosis of the femoral head].
To investigate the operative method of trabecular metal rod implant for the treatment of the early adult avascular necrosis of the femoral head (ANFH) and its clinical efficacy. From March 2005 to January 2007, 28 patients of ANFH were treated by trabecular metal rod implant, including 18 males and 10 females aged 18- 56-years-old (average 30.6-years-old). The ANFH was induced by trauma in 7 cases, steroid in 10 cases, alcohol in 5 cases and unknown reason in 6 cases. There were 22 cases of unilateral ANFH and 6 of bilateral ANFH, involving 18 left hips and 16 right hips. According to Association Research Circulation Osseous (ARCO) international classification of osteonecrosis launched in 1997, 16 cases (16 hips) were classified as stage I, 12 cases (15 hips) as stage II, 1 case (1 hip) as stage III and 2 cases (2 hips) as stage IV. Harris score was 50.3 +/- 2.2 preoperatively. The course of disease was 12-24 months (average 16 months). All wounds healed by first intention, and no postoperative complication occurred. All the cases were followed up for 18-36 months (average 26 months). The pain and functional limitation of patients were improved significantly. The Harris score was 85.7 +/- 2.4 18 months after operation, showing a significant difference when compared with preoperative score (P < 0.05). Twenty-three cases were graded as excellent, 3 as good and 2 as fair, with the excellent and good rate of 92.86%. Trabecular metal rod implant is an effective method for the treatment of early ANFH and can minimize the occurrence of complications, but the follow-up observation of its long-term therapeutic effect is still needed.


Thrombocytopenia in dogs with anticoagulant rodenticide-induced hemorrhage: eight cases (1990-1995).
Thrombocytopenia was documented in eight of 11 dogs with anticoagulant rodenticide-induced hemorrhage. Thrombocytopenia was transient and generally mild-to-moderate, but it became marked (i.e., less than 30,000 platelets/microl) in two cases. Petechial hemorrhages were not noted in any case. There was no relationship between hematocrit and platelet count. Platelet count changes in response to treatment with fresh-frozen plasma and isotonic electrolyte solutions were variable. Anticoagulant rodenticide toxicity should be included as a differential diagnosis for dogs with hemorrhage accompanied by mild-to-moderate thrombocytopenia.


Ketogenic diet for refractory epilepsy with MEHMO syndrome: Caution for acute necrotizing pancreatitis.
The MEHMO (mental retardation, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity) syndrome, which is caused by a hemizygous variant in the EIF2S3 gene on chromosome Xp22, is associated with significant morbidity and mortality. Refractory epileptic seizures and glucose dysregulation are characteristic manifestations of the MEHMO syndrome, which can often diminish patients' quality of life. A 5-year-old boy was referred to our hospital because of profound intellectual disability, micropenis, cryptorchidism, central hypothyroidism, and microcephaly. He had neonatal hypoglycemia at birth and later experienced refractory epileptic seizures and developed obesity and insulin-dependent diabetes. A diagnosis of MEHMO syndrome was established on the basis of the patient's clinical manifestations and de novo novel missense variant in the EIF2S3 gene (NM_001415.3:c.805 T > G) that was detected through whole-exome analysis. Although the patient's refractory seizures and diabetes had been well controlled with a combination of ketogenic diet (KD) therapy and insulin therapy, acute fatal necrotizing pancreatitis occurred at the age of 68 months. Moreover, despite intensive care, his condition rapidly deteriorated to multiple organ failure and acute respiratory distress syndrome, resulting in death. The pathophysiology of glucose intolerance in MEHMO syndrome remains to be elucidated; however, recent studies have suggested that EIF2S3 gene variants could lead to glucose dysregulation and β-cell damage in the pancreas. We suspect that in the present case, KD therapy led to an abnormal load on the beta cells that were damaged owing to eIF2γ dysfunction. Therefore, the adverse effects of KD in patients with MEHMO syndrome should be considered.


Psychiatric disorders and functioning in hepatitis B virus carriers.
The authors compared asymptomatic hepatitis B virus carriers and healthy subjects in terms of their psychological state. Participants (43 asymptomatic hepatitis B virus carriers and 43 healthy comparison subjects) completed self-report questionnaires. Psychiatric disorders and psychosocial functioning were evaluated with structured clinical interviews and the Global Assessment of Functioning scale. Hepatitis B virus carriers were more likely to have psychiatric disorders than comparison subjects (30.2% vs. 11.6%). Also, carriers had significantly higher depression and anxiety scores and lower Global Assessment of Functioning scores than did comparison subjects. Worries about contamination and illnesses related to hepatitis B infection were associated with the presence of psychiatric disorder. The results suggest that asymptomatic hepatitis B virus carriers need emotional support.


Prions spread via the autonomic nervous system from the gut to the central nervous system in cattle incubating bovine spongiform encephalopathy.
To elucidate the still-unknown pathogenesis of bovine spongiform encephalopathy (BSE), an oral BSE challenge and sequential kill study was carried out on 56 calves. Relevant tissues belonging to the peripheral and central nervous system, as well as to the lymphoreticular tract, from necropsied animals were analysed by highly sensitive immunohistochemistry and immunoblotting techniques to reveal the presence of BSE-associated pathological prion protein (PrPSc) depositions. Our results demonstrate two routes involving the autonomic nervous system through which BSE prions spread by anterograde pathways from the gastrointestinal tract (GIT) to the central nervous system (CNS): (i) via the coeliac and mesenteric ganglion complex, splanchnic nerves and the lumbal/caudal thoracic spinal cord (representing the sympathetic GIT innervation); and (ii) via the Nervus vagus (parasympathetic GIT innervation). The dorsal root ganglia seem to be subsequently affected, so it is likely that BSE prion invasion of the non-autonomic peripheral nervous system (e.g. sciatic nerve) is a secondary retrograde event following prion replication in the CNS. Moreover, BSE-associated PrPSc was already detected in the brainstem of an animal 24 months post-infection, which is 8 months earlier than reported previously. These findings are important for the understanding of BSE pathogenesis and for the development of new diagnostic strategies for this infectious disease.


High-Polarity Fluoroalkyl Ether Electrolyte Enables Solvation-Free Li+ Transfer for High-Rate Lithium Metal Batteries.
Lithium metal batteries (LMBs) have aroused extensive interest in the field of energy storage owing to the ultrahigh anode capacity. However, strong solvation of Li+ and slow interfacial ion transfer associated with conventional electrolytes limit their long-cycle and high-rate capabilities. Herein an electrolyte system based on fluoroalkyl ether 2,2,2-trifluoroethyl-1,1,2,3,3,3-hexafluoropropyl ether (THE) and ether electrolytes is designed to effectively upgrade the long-cycle and high-rate performances of LMBs. THE owns large adsorption energy with ether-based solvents, thus reducing Li+ interaction and solvation in ether electrolytes. With THE rich in fluoroalkyl groups adjacent to oxygen atoms, the electrolyte owns ultrahigh polarity, enabling solvation-free Li+ transfer with a substantially decreased energy barrier and ten times enhancement in Li+ transference at the electrolyte/anode interface. In addition, the uniform adsorption of fluorine-rich THE on the anode and subsequent LiF formation suppress dendrite formation and stabilize the solid electrolyte interphase layer. With the electrolyte, the lithium metal battery with a LiFePO4 cathode delivers unprecedented cyclic performances with only 0.0012% capacity loss per cycle over 5000 cycles at 10 C. Such enhancement is consistently observed for LMBs with other mainstream electrodes including LiCoO2 and LiNi0.5 Mn0.3 Co0.2 O2 , suggesting the generality of the electrolyte design for battery applications.


Flavonoid C-glucosides Derived from Flax Straw Extracts Reduce Human Breast Cancer Cell Growth In vitro and Induce Apoptosis.
Flax straw of flax varieties that are grown for oil production is a by product which represents a considerable biomass source. Therefore, its potential application for human use is of high interest. Our research has revealed that flax straw is rich in flavonoid C-glucosides, including vitexin, orientin, and isoorientin. The objective of this study was to evaluate the cytotoxicity and possible proapoptotic effect of flax straw derived C-glucosides of flavonoids in the human breast adenocarcinoma cell line (MCF-7). The effects of flax straw derived flavonoid C-glucosides on cell proliferation of MCF-7 cells were evaluated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) and sulforhodamine B assays. The expression of apoptosis-related genes was assessed by real-time PCR. Our data revealed that flax C-glucosides as well as pure compounds are cytotoxic toward MCF-7 cells and inhibit their proliferation. Moreover, the induction of apoptosis was correlated with the changes in the mRNA level of pro-apoptotic genes. Increased expression of bax and caspase-7, -8, and -9 and decreased mRNA expression of bcl-2 was observed, whereas the mRNA levels of p53 and mdm2 were not altered. These results clearly demonstrated that flax straw metabolites effectively induced growth inhibition and apoptosis in human breast adenocarcinoma cells.


Pediatric HIV Infection.
HIV infection by maternal transmission is increasing in the world due to the increase in infected women who are not receiving appropriate antiretroviral therapy. Prognosis of HIV infection in children is poor because the newborn has an immature immune system. Early diagnosis and therapy are needed to avoid the development of AIDS. New therapies are becoming available but prevention of infection, through maternal therapy during pregnancy, is the most effective measure in avoiding this infection through this transmission route.


Pharmacokinetics of darunavir at 900 milligrams and ritonavir at 100 milligrams once daily when coadministered with efavirenz at 600 milligrams once daily in healthy volunteers.
Ritonavir-boosted darunavir with efavirenz may be considered a nucleoside-sparing regimen for treatment-naïve HIV-infected patients. However, the pharmacokinetics of this combination administered once daily have not been studied. We conducted a three-period interaction study with healthy volunteers. The subjects were given darunavir at 900 mg with ritonavir at 100 mg once daily for 10 days. Efavirenz at 600 mg once daily was added for 14 days. Darunavir-ritonavir was then stopped and efavirenz alone was given for 14 days. At the end of each period, blood was taken predosing and for up to 24 h postdosing to measure the drug concentrations. We recruited seven males and five females ages 24 to 49 years and weighing 50 to 83 kg. The darunavir trough concentrations were reduced after efavirenz administration (geometric mean ratio [GMR], 0.43; 90% confidence interval [CI], 0.32 to 0.57]; P < 0.001). The mean darunavir trough concentrations were 1,180 ng/ml (standard deviation, 1,138 ng/ml) after efavirenz administration, but all darunavir trough concentrations were above the 50% effective concentration (EC(50)) of 55 ng/ml for the wild-type virus. For darunavir, the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) (GMR, 0.86; 90% CI, 0.75 to 0.97; P = 0.05) and the half-life (GMR, 0.56; 90% CI, 0.49 to 0.65; P < 0.001) were also significantly reduced. The darunavir peak concentrations were not significantly changed (GMR, 0.92; 90% CI, 0.82 to 1.03; P = 0.23). The ritonavir trough concentrations (GMR, 0.46; 90% CI, 0.33 to 0.63; P = 0.001), AUC(0-24) (GMR, 0.74; 90% CI, 0.64 to 0.86; P = 0.004), and half-life (GMR, 0.80; 90% CI, 0.75 to 0.86; P < 0.001) were also significantly reduced. The efavirenz half-life was significantly longer when it was coadministered with darunavir-ritonavir than when it was given alone (GMR, 1.66; 90% CI, 1.24 to 2.23; P = 0.01), but there were no differences in the efavirenz trough or peak concentration or AUC(0-24) when it was coadministered with darunavir-ritonavir. Efavirenz reduced the trough concentrations of darunavir significantly, but the concentrations remained above the EC(50) for the wild-type virus. This regimen should be evaluated with treatment-naïve patients with no preexisting resistance.


Cognitive switching processes in young people with attention-deficit/hyperactivity disorder.
Patients with attention-deficit/hyperactivity disorder (ADHD) can be slow at switching between stimuli, or between sets of stimuli to control behaviour appropriate to changing situations. We examined clinical and experimental parameters that may influence the speed of such processes measured in the trail-making (TMT) and switch-tasks in cases with ADHD combined type, their non-affected siblings and unrelated healthy controls. The latency for completion of the trail-making task controlling for psychomotor processing (TMT-B-A) was longer for ADHD cases, and correlated with Conners' ratings of symptom severity across all subjects. The effect decreased with age. Switch-task responses to questions of "Which number?" and "How many?" between sets of 1/111 or 3/333 elicited differential increases in latency with condition that affected all groups. But there was evidence for increased symptom-related intra-individual variability among the ADHD cases, and across all subjects. Young siblings showed familiality for some measures of TMT and switch-task performance but these were modest. The potential influences of moderator variables on the efficiency of processing stimulus change rather than the speed of processing are discussed.


Case Report: Paucisymptomatic College-Age Population as a Reservoir for Potentially Neutralization-Resistant Severe Acute Respiratory Syndrome Coronavirus 2 Variants.
To better understand the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant lineage distribution in a college campus population, we carried out viral genome surveillance over a 7-week period from January to March 2021. Among the sequences were three novel viral variants: BV-1 with a B.1.1.7/20I genetic background and an additional spike mutation Q493R, associated with a mild but longer-than-usual COVID-19 case in a college-age person, BV-2 with a T478K mutation on a 20B genetic background, and BV-3, an apparent recombinant lineage. This work highlights the potential of an undervaccinated younger population as a reservoir for the spread and generation of novel variants. This also demonstrates the value of whole genome sequencing as a routine disease surveillance tool.


The challenges in the diagnosis of detrusor underactivity in clinical practice: A mini-review.
To review the current definitions, terminology, epidemiology and aetiology of detrusor underactivity (DU), with specific attention to the diagnostic criteria in use. In addition, we address the relation and the overlap between DU and bladder outlet obstruction (BOO). In this mini-review, we hope to help identify DU patients and facilitate structured clinical evaluation and research. We searched the English literature using ScienceDirect and PubMed for relevant articles. We used the following terms: 'detrusor underactivity', 'underactive bladder', 'post voiding residual', 'post micturition residual', 'acontractile bladder', 'detrusor failure', and 'detrusor areflexia'. DU is one of the most common conditions causing lower urinary tract symptoms (LUTS). Unfortunately, it is also the most poorly understood bladder dysfunction with scant research. To our knowledge there is no clear definition and no non-invasive method to characterise this important clinical condition. DU may result from the normal ageing process; however, it has multiple aetiologies including neurogenic and myogenic dysfunction. In many cases the symptoms of DU are similar to those of BOO and it usually requires invasive urodynamic study (UDS) for diagnosis to differentiate the two diagnoses. A number of diagnostic tests may be used including: UDS testing, the Schafer pressure/flow nomogram, linear passive urethral resistance relation, Watts factor, and the bladder contractility index. Of these, UDS testing is the most practical as it determines both the maximum urinary flow rate and the pressure exerted by the detrusor muscle relative to the maximal flow of urine, allowing for precise characterisation of detrusor function. Currently, the diagnosis of DU is based on invasive urodynamic parameters as defined by the International Continence Society in 2002. There is no consensus for the definition of DU prior to 2002. As there is significant overlap between the symptoms of DU and BOO, it is difficult to diagnose DU clinically.


[Prognostic factors and results of external irradiation of cancers of the base of the tongue].
At the Curie Institute, between 1958-1980, 166 patients were treated for squamous cell carcinoma of the base of the tongue, by external radiotherapy alone. The absolute survival was 45%, 39%, 26% at 2, 3, 5 years. 95% local and loco-regional failures arrived within the first two years; the nodal failures isolated were rare (4%). Unfavorable prognosis features are: the size of the tumor and the clinical radiation-induced regression of the primary. A new therapeutic approach is discussed: an additive curietherapy for some T1-T2 and a surgical excision (total glossectomy with or without neck dissection) for some T3-T4 of which the regression is unsatisfactory at 50-55 Gy are proposed.


Identification, characterization, and expression of dentin matrix protein 1 gene in Xenopus laevis.
Dentin matrix protein 1 (DMP1) is an acidic extracellular matrix protein expressed mainly in bone and dentin, and is a member of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family. The DMP1 gene, however, appears to evolve rapidly in comparison with other SIBLING genes, even though such functionally important molecules usually evolve more slowly than less important ones. The purpose of this study was to identify and characterize an ortholog of the DMP1 gene in an amphibian (Xenopus laevis; X. laevis) to clarify molecular evolutionary alterations in DMP1 associated with calcified tissues in tetrapods. Furthermore, we analyzed the mRNA expression of this gene to elucidate its functional change in bone and developing tooth germ in comparison with amniote DMP1s. The similarities of the deduced amino acid sequence of X. laevis DMP1 to that of the corresponding amniote proteins were low, although they did share several unique features specific to DMP1 and have similar properties. Expression of X. laevis DMP1 mRNA was predominant in osteocytes and odontoblasts, but only transiently observed in ameloblasts, as in amniotes. These results suggest that DMP1 has conserved several functions during tetrapod evolution. This indicates that continuity of biochemical properties has been more important in maintaining DMP1 functionality than that of the sequence of amino acid residues, which has undergone change over the course of molecular evolution.


[Requirements of turkeys kept on the ground with respect to energy and crude protein content of mixed feeds].
In four experiments with 9,500 turkeys assorted according to sex, three energy levels (500, 550 and 600 EFh (energetic feed units for hens = 14,6 kJ net energy body fat of hens)/kg feed) were combined with three levels of crude protein (250, 300 and 350 g/kg feed) in the mixed feed (9 rations) and tested under conditions of keeping the turkeys on the ground from hatching to their 42nd day of life. The feed consumption of the turkeys did not correlate with the energy content of the mixed feed. The energy consumption of the groups whose mixed feed had a high energy content (550 and 600 EFh) was significantly higher than that of groups whose feed had a low energy content. With the increasing content of crude protein in the mixed feed the consumption of crude protein per turkey and test period rose significantly. Due to the increase of the content of energy and crude protein, the live weight gain increased after a 28- and 42-day test period; the growth-stimulating effect was more distinct with male animals. Mortality had no connections with nutrition. For the starting-off feed for turkeys an energy content of < 580 EFh with 300 g crude protein per kg mixed feed up to the 4th/5th week of life is recommended.


Gut Microbiome and Associated Metabolites Following Bariatric Surgery and Comparison to Healthy Controls.
The gut microbiome plays a significant role in regulating the host's ability to store fat, which impacts the development of obesity. This observational cohort study recruited obese adult men and women scheduled to undergo sleeve gastrectomy and followed up with them 6 months post-surgery to analyse their microbial taxonomic profiles and associated metabolites in comparison to a healthy control group. There were no significant differences in the gut bacterial diversity between the bariatric patients at baseline and at follow-up or between the bariatric patients and the cohort of healthy controls. However, there were differential abundances in specific bacterial groups between the two cohorts. The bariatric patients were observed to have significant enrichment in Granulicatella at baseline and Streptococcus and Actinomyces at follow-up compared to the healthy controls. Several operational taxonomic units assigned to commensal Clostridia were significantly reduced in the stool of bariatric patients both at baseline and follow-up. When compared to a healthy cohort, the plasma levels of the short chain fatty acid acetate were significantly higher in the bariatric surgery group at baseline. This remained significant when adjusted for age and sex (p = 0.013). The levels of soluble CD14 and CD163 were significantly higher (p = 0.0432 and p = 0.0067, respectively) in the bariatric surgery patients compared to the healthy controls at baseline. The present study demonstrated that there are alterations in the abundance of certain bacterial groups in the gut microbiome of obese patients prior to bariatric surgery compared to healthy individuals, which persist post-sleeve gastrectomy.


The septic shock-associated IL-10 -1082 A > G polymorphism mediates allele-specific transcription via poly(ADP-Ribose) polymerase 1 in macrophages engulfing apoptotic cells.
The biallelic IL-10 single nucleotide polymorphism at -1082 of the promoter region linked to individual variation in cytokine inducibility has been strongly implicated in several pathological conditions including the development of, and outcomes in, septic shock during pneumococcal infection, acute respiratory distress syndrome, and cardiac dysfunction. However, the molecular basis of the single nucleotide polymorphism-mediated variable IL-10 production levels has not been explored. In this study, we report that the -1082G > A alleles in the promoter region of the human IL-10 gene physically interact with a nuclear protein in an allele-specific manner that results in different levels of IL-10 transcription. This protein has been identified as poly(ADP-ribose) polymerase 1 (PARP-1). We show that PARP-1 acts as a transcription repressor, and its DNA-binding activity is strongly regulated in macrophages that engulf apoptotic cells but not stimulated with LPS. These findings unveil a novel role of PARP-1 in the regulation of IL-10 production in an allele-dependent way, which determines individual susceptibility to sepsis-induced inflammatory pathology and the immunological sequelae in a physiological process in which clearance of infection-induced apoptotic cells by professional phagocytes triggers the cytokine synthesis.


Laboratory studies of the effects of reduced prey choice caused by Bt plants on a predatory insect.
Crops transformed to express Bacillus thuringiensis (Bt) toxins can cause close to 100% mortality of certain target pest species. This study assessed the effect of target pest reduction on the predatory insect Chrysoperla carnea (Stephens) in the presence of alternative prey. Numbers of lacewings recovered from Bt oilseed rape (cultivar Oscar, event O52) did not differ significantly from numbers of lacewings recovered from conventional oilseed rape in cage experiments with the target pest Plutella xylostella (Linnaeus) and the non-target pest Myzus persicae (Sulzer) when aphid densities were high. However, significantly fewer lacewings were recovered from Bt plants as aphid densities were lowered. Lacewing weights were not affected by plant type.


Lack of outcome benefit and clopidogrel "resistance." The TRITON trial challenge.
Impaired response to clopidogrel, or "resistance" is a cornerstone concept for justification of more aggressive antiplatelet regimens, and development of new more potent drugs. There are over 1,000 citations (although predominantly reviews, or case reports) in MEDLINE related to clopidogrel "resistance", while about 100 of them attempted to link low response to adverse clinical outcomes. However, most of these studies are woefully small, and not randomised. The TRITON trial assessed head-to-head novel antiplatelet agent prasugrel versus clopidogrel in patients with acute coronary syndromes. This study was the first in a decade to challenge clopidogrel monopoly, and to indirectly test the "resistance" hypothesis. The primary endpoint was the rate of cardiovascular death, non-fatal myocardial infarction, or stroke, and occurred in 12.1% of patients treated with clopidogrel, and 9.9% of patients randomised to prasugrel, suggesting impressive vascular outcome benefit of prasugrel over clopidogrel. However, the Food and Drug Administration (FDA) presented more balanced, and realistic outlook on TRITON. While very early periprocedural benefit exists, long-term prasugrel therapy yielded identical to clopidogrel vascular outcomes among 13,608 TRITON patients challenging the postulate that clopidogrel "resistance" phenomenon is clinically relevant. Despite the fact that prasugrel 10 mg/daily cause 2.5 times more potent platelet inhibition than conventional clopidogrel 75 mg/daily, with fewer patients exhibiting broad response variability, and/or antiplatelet "resistance", the vascular benefit beyond acute phase was identical. Keeping in mind growing over time bleeding, cancer, and mortality risks associated with chronic prasugrel use, small observational studies should be judged with skepticism as hypothesis-generating, pending confirmation in randomised trials.


Basonuclin is associated with the ribosomal RNA genes on human keratinocyte mitotic chromosomes.
Basonuclin is a zinc finger protein mainly expressed in keratinocytes of the basal layer of epidermis and the outer root sheath of hair follicles. It is also found in abundance in the germ cells of testis and ovary. In cultured keratinocytes, basonuclin is associated with chromatin in all phases of the cell cycle, including mitosis. By immunocytochemical methods, we demonstrate here that in mitosis basonuclin is associated with the short arms of the acrocentric chromosomes and with other loci on many metaphase chromosomes of human keratinocytes. Using the evolutionarily highly conserved N-terminal pair of zinc fingers in an electrophoresis mobility shift assay, we demonstrate that the DNA target sequences of basonuclin on the acrocentric chromosomes are likely to be within the promoter region of the 45S rRNA gene transcription unit. DNase I footprinting shows that basonuclin zinc fingers interact with the upstream control element of this promoter, which is necessary for the high level of transcription of the rRNA genes. This result suggests that basonuclin may be a tissue-specific transcription factor for the ribosomal RNA genes.


Low stroma androgen receptor level in normal and tumor prostate tissue is related to poor outcome in prostate cancer patients.
The role of androgen receptors (ARs) in the prostate tumor cell environment is largely unknown. AR immunostaining was evaluated in relation to stroma morphology, expression of AR co-activator ARA55, tumor characteristics and clinical outcome in normal and prostate cancer (PCa) tissue obtained at transurethral resection in men treated with expectancy, and in diagnostic transrectal core biopsies in men treated with surgical castration. Stroma composition was studied by Masson-trichrome and desmin staining. Levels of AR and ARA55 mRNA were quantified by laser micro-dissection and RT-PCR. The percentage of cells with positive nuclear AR immunostaining in the tumor and normal stroma was inversely related to Gleason score, tumor size, tumor stage, metastasis, response to castration therapy, and cancer-specific survival. The AR staining in the normal stroma provided independent prognostic information in Cox multiple linear regression analysis. Loss of stroma AR staining was linked to low expression of ARA55 in stroma smooth muscle cells, and in tumors also to gradual disappearance of this cell type. PCa aggressiveness and efficacy of castration therapy are related to AR levels in the tumor stroma and importantly to AR levels in the surrounding normal prostate tissue stroma. .


Associations among chronic disease status, participation in federal nutrition programs, food insecurity, and sugar-sweetened beverage and water intake among residents of a health-disparate region.
To determine whether sociodemographic characteristics, food security status, participation in federal nutrition programs (Supplemental Nutrition Assistance Program [SNAP] or Special Supplemental Nutrition Program for Women, Infants, and Children [WIC]), and chronic disease status were associated with adherence to water and sugar-sweetened beverage (SSB) intake recommendations. Cross-sectional, random-digit phone survey with questions from the Behavioral Risk Factor Surveillance System and beverage intake questionnaire. Residents of a medically underserved, rural area. Water and SSB intake. Descriptive statistics, chi-square and 1-way ANOVA, and linear and logistic regression. The sample consisted of 930 respondents (aged 56 ± 17 years; 35% non-white); reported food insecurity and SNAP and WIC participation were 37%, 29%, and 8%, respectively. Prevalent health conditions included overweight/obesity (69%), diabetes (19%), and hypertension (45%). Water recommendations were more likely to be met (72%; mean intake, 31 ± 19 fluid oz) than SSB (41%; mean intake, 246 ± 297 kcal). Food insecurity and SNAP/WIC participation were not associated with meeting recommendations, but those reporting ≥ 1 chronic disease were more likely to meet SSB recommendations (odds ratio, 2.42; P = .02). Odds of achieving SSB but not water recommendations were greater among individuals with a chronic disease. Efforts to communicate beverage recommendations to at-risk groups are needed.


Oncogenic RAS-induced downregulation of ATG12 is required for survival of malignant intestinal epithelial cells.
Activating mutations of RAS GTPase contribute to the progression of many cancers, including colorectal carcinoma. So far, attempts to develop treatments of mutant RAS-carrying cancers have been unsuccessful due to insufficient understanding of the salient mechanisms of RAS signaling. We found that RAS downregulates the protein ATG12 in colon cancer cells. ATG12 is a mediator of autophagy, a process of degradation and reutilization of cellular components. In addition, ATG12 can kill cells via autophagy-independent mechanisms. We established that RAS reduces ATG12 levels in cancer cells by accelerating its proteasomal degradation. We further observed that RAS-dependent ATG12 loss in these cells is mediated by protein kinases MAP2K/MEK and MAPK1/ERK2-MAPK3/ERK1, known effectors of RAS. We also demonstrated that the reversal of the effect of RAS on ATG12 achieved by the expression of exogenous ATG12 in cancer cells triggers both apoptotic and nonapoptotic signals and efficiently kills the cells. ATG12 is known to promote autophagy by forming covalent complexes with other autophagy mediators, such as ATG5. We found that the ability of ATG12 to kill oncogenic RAS-carrying malignant cells does not require covalent binding of ATG12 to other proteins. In summary, we have identified a novel mechanism by which oncogenic RAS promotes survival of malignant intestinal epithelial cells. This mechanism is driven by RAS-dependent loss of ATG12 in these cells.


Large-scale somatotopic refinement via functional synapse elimination in the sensory thalamus of developing mice.
Functional synapse elimination and strengthening are crucial developmental processes in the formation of precise neuronal circuits in the somatosensory system, but the underlying alterations in topographical organization are not yet fully understood. To address this issue, we generated transgenic mice in which afferent fibers originating from the whisker-related brain region, called the maxillary principal trigeminal nucleus (PrV2), were selectively visualized with genetically expressed fluorescent protein. We found that functional synapse elimination drove and established large-scale somatotopic refinement even after the thalamic barreloid architecture was formed. Before functional synapse elimination, the whisker sensory thalamus was innervated by afferent fibers not only from the PrV2, but also from the brainstem nuclei representing other body parts. Most notably, only afferent fibers from PrV2 onto a whisker sensory thalamic neuron selectively survived and were strengthened, whereas other afferent fibers were preferentially eliminated via their functional synapse elimination. This large-scale somatotopic refinement was at least partially dependent on somatosensory experience. These novel results uncovered a previously unrecognized role of developmental synapse elimination in the large-scale, instead of the fine-scale, somatotopic refinement even after the initial segregation of the barreloid map.