The Aspergillus nidulans bimE (blocked-in-mitosis) gene encodes multiple cell cycle functions involved in mitotic checkpoint control and mitosis.
The bimE (blocked-in-mitosis) gene appears to function as a negative mitotic regulator because the recessive bimE7 mutation can override certain interphase-arresting treatments and mutations, causing abnormal induction of mitosis. We have further investigated the role of bimE in cell cycle checkpoint control by: (1) coordinately measuring mitotic induction and DNA content of bimE7 mutant cells; and (2) analyzing epistasis relationships between bimE7 and 16 different nim mutations. A combination of cytological and flow cytometric techniques was used to show that bimE7 cells at restrictive temperature (44 degrees C) undergo a normal, although somewhat slower cell cycle prior to mitotic arrest. Most bimE7 cells were fully reversible from restrictive temperature arrest, indicating that they are able to enter mitosis normally, and therefore require bimE function in order to finish mitosis. Furthermore, epistasis studies between bimE7 and mutations in cdc2 pathway components revealed that the induction of mitosis caused by inactivation of bimE requires functional p34cdc2 kinase, and that mitotic induction by bimE7 depends upon several other nim genes whose functions are not yet known. The involvement of bimE in S phase function and mitotic checkpoint control was suggested by three lines of evidence. First, at restrictive temperature the bimE7 mutation slowed the cell cycle by delaying the onset or execution of S phase. Second, at permissive temperature (30 degrees C) the bimE7 mutation conferred enhanced sensitivity to the DNA synthesis inhibitor hydroxyurea. Finally, the checkpoint linking M phase to the completion of S phase was abolished when bimE7 was combined with two nim mutations that cause arrest in G1 or S phase. A model for bimE function based on these findings is presented.


Palladium-catalyzed coupling of ammonia and lithium amide with aryl halides.
A mild, palladium-catalyzed coupling of aryl halides with ammonia or lithium amide to form primary arylamines as the major product is described. These reactions occurred with excellent selectivity for formation of the primary arylamine over formation of the diarylamine (9.5:1 to over 50:1 ratios of arylamine to diarylamine). In addition, the first organopalladium complex with a terminal -NH2 ligand has been isolated. This complex reductively eliminates to form arylamines.


Phylogeny of DNA polymerase-beta.
Analyses of various organisms for DNA polymerase-beta activity show that the enzyme is widely distributed in cells from multicellular animals but absent in bacteria, plants, and protozoa. These results suggest that DNA polymerase-beta may have evolved with the development of metazoan forms. Further evolutionary changes of the enzyme protein may account for some of the minor differences in properties of the enzyme in various organisms.


Nutritional knowledge of youth academy athletes.
Youth athletes are under increasing pressures to excel in their chosen sport and many turn to nutritional supplements in order to enhance sports performance. However, athletes may obtain their nutritional information via illegitimate sources such as the internet, media, and other athletes, representing miscommunication between sound scientific information and anecdotal experiences. The objective of this investigation was to examine nutrition knowledge of elite youth athletes from a non-residential regional academy of sport. A previously validated two-part nutrition knowledge questionnaire (NKQ) was administered to 101 (37 male and 64 female) non-residential regional Academy of Sport elite youth athletes at an annual training camp. Part 1 of the NKQ presented demographic questions. Part 2 presented 90 sports nutrition knowledge questions in seven knowledge subcategories (1) Nutrients; (2) Dietary reference intakes (DRI); (3) Fluids/Hydration; (4) Recovery; (5) Weight gain; (6) Weight loss; and (7) Supplements. The mean NKQ score of all athletes was 43.8% (± 11.4). No gender differences observed between nutritional knowledge total scores, however female athletes recorded more 'correct' responses than males (p = 0.02) in the Nutrients subcategory. Majority of athletes had difficulty identifying correct DRI with this subcategory featuring the lowest percentage of 'correct' to 'incorrect' responses (27.1% ± 2.3; p = 0.02). Supplements subcategory displayed much uncertainty with significantly more 'unsure' than 'incorrect' responses (42.4% ± 20.3; p < 0.05). In agreement with previous research, results of the current study indicate that elite youth athletes lack fundamental nutritional knowledge, specifically related to DRI and supplementation. These data provide further support of current recommendations that Academy of Sport youth athletes may benefit from integrated nutrition education conducted by qualified nutrition professionals.


Utilizing virtual surgical planning and orthognathic surgery to correct severe facial asymmetry without orthodontic treatment.
Combining double-jaw surgery and orthodontic treatment to correct dentofacial asymmetry is a standard procedure but time consuming and costly. In order to provide alternative solutions, previewing the possible results with precise virtual surgical planning (VSP) system can help clinicians select patients suited for correcting facial asymmetry surgically without orthodontic treatment. In our experiences, after rigid or semirigid fixation of the maxilla, using intermaxillary fixation (IMF) without mandibular bony fixation is another key. This kind of fixation can minimize the chances of changing the condylar position and occlusion after the rotation of the maxillomandibular complex. If the original occlusion can be maintained, then orthodontic treatment can be avoided. Here we presented two facial asymmetry cases who requested surgical correction and refused orthodontic treatment. With careful preoperative planning using VSP, double-jaw surgery with maxillary bony fixation and IMF was conducted and both patients were satisfied by their aesthetic outcomes. With minimal dental compensation, the long-term results were relatively stable.


Salivary DNA methylation markers for cancer of oral cavity.
Aberrant DNA methylation plays a crucial role in oral carcinogenesis. Our previous study demonstrated hypermethylation of DAPK1, LRPPRC, RAB6C, and ZNF471 promoters in patients with tongue squamous cell carcinoma compared with normal samples. Methylation profiling using salivary DNA is considered a non-invasive alternative to tissue samples. Hence, the present study tested the DNA methylation status of these four promoters as indicators of oral cancer progression. We performed the bisulfite-based targeted next-generation sequencing of four candidate genes in saliva and tissue DNA from normal, premalignant, and squamous cell carcinoma subjects. The clinicopathological association, diagnostic, and prognostic utility of aberrant DNA methylation were evaluated using the TCGA-HNSCC dataset. Using the Xgboost algorithm and logistic regression, CpG sites were prioritized, and Receiver Operating Characteristic was generated. By Log-rank test and Kaplan-Meier (KM) curves, an association between methylation and overall survival (OS), disease-free interval (DFI), and progression-free interval (PFI) were computed. We identified all four genes as significantly hypermethylated in premalignant and malignant samples compared with normal samples. The methylation levels were comparable between saliva and tissue samples with an r-value of 0.6297 to 0.8023 and 0.7823 to 0.9419 between premalignant tissue vs. saliva and OC vs. saliva, respectively. We identified an inverse correlation between DAPK1, LRPPRC, RAB6C, and ZNF471 promoter methylation with their expression. A classifier of 8 differentially methylated CpG sites belonging to DAPK1, RAB6C, and ZNF471 promoters was constructed, showing an AUC of 0.984 to differentiate tumors from normal samples. The differential methylation status of DAPK1, LRPPRC, and ZNF71 promoters was prognostically important. Abnormal expression of all four genes was associated with immune infiltration. Thus, methylation analysis of these candidate CpG sites from saliva can be helpful as a non-invasive tool for the clinical management of OC.


Phosphaturic mesenchymal tumor, an unusual localization in head and neck.
Phosphaturic mesenchymal tumor (PMT) is a rare mesenchymal neoplasm associated with tumor-induced osteomalacia involving bone and soft tissue that produces paraneoplastic hypophosphatemic osteomalacia. The common physiologic defect in this conditions involves an impairment in renal tubular phosphate reabsorption with a downregulation of renal 1α-hydroxylase activity, while calcium metabolism remains essentially unaffected. Microscopic features consist of spindle cells, multinucleated giant cells and calcifications embedded in a chondromyxoid matrix with variable cellularity and prominent vascularity. Approximately 95% of PMTs involve the extremities and appendicular skeleton, with only 5% occurring in the head and neck region. Localization in the head and neck is pretty uncommon, nose and paranasal sinuses are preferentially affected. Due to its rarity, the purpose of the study was to report a new case of PMT whose locations in temporomandibular joint was never reported in literature.


Relationships between micronutrient losses in sweat and blood pressure among heat-exposed steelworkers.
We aimed to examine the effect of micronutrient losses through sweat on blood pressure (BP) among heat-exposed steelworkers. A total of 224 heat-exposed male steelworkers from an ironworks facility were evaluated in July 2012. We measured the Wet Bulb Globe Temperature Index to evaluate the level of heat stress in the workplace. We collected sweat from the workers during an eight-hour work, and then we measured the micronutrients in the sweat. We also measured the BP of each worker. The results revealed that vitamin C, potassium, and calcium losses in sweat were positively correlated with systolic (SBP) and diastolic (DBP) blood pressure (all P<0.05). A linear stepwise regression analysis revealed that potassium, and calcium losses in sweat adversely affected SBP and DBP (all P<0.05). An analysis of covariance showed that SBP increased when potassium or calcium losses in sweat were >900 mg, or >100 mg, respectively. Further, DBP increased when potassium or calcium losses in sweat were >600 mg or >130 mg, respectively. Therefore, vitamin C, potassium, and calcium losses in sweat may adversely effect BP. To help steelworkers maintain healthy BP, facilities with high temperatures should try to lower environmental temperatures to reduce vitamin C, potassium, and calcium losses in sweat. Additionally, heat-exposed steelworkers may need to increase their dietary intakes of vitamin C, potassium, and calcium. Further research is needed to confirm these findings and support these recommendations.


Dating app use and unhealthy weight control behaviors among a sample of U.S. adults: a cross-sectional study.
Online dating has become increasingly popular over the years. Few research studies have examined the association between dating apps and disordered eating. In this study, we evaluated the association between dating app use and unhealthy weight control behaviors (UWCBs) among a sample of U.S. adults. Our sample includes 1769 adults who completed an online survey assessing dating app use and UWCBs in the past year. Survey assessed participants' self-reported frequency of using dating apps within the past 30 days and engagement in six UWCBs with the purpose of lowering weight or changing their body shape within the past 12 months. UWCBs included vomiting, laxative use, fasting, diet pill use, muscle building supplement use, and use of anabolic steroids. Results of multivariate logistic regression models suggest dating app users had substantially elevated odds of UWCBs compared with non-users (odds ratios [OR] range = 2.7-16.2). These findings were supported by results of additional gender-stratified multivariate logistic regression analyses among women and men. This study's findings contribute to the limited literature exploring the association between dating app use and adverse health outcomes, particularly UWCBs. While additional longitudinal and representative research is needed, public health professionals ought to explore dating app use as a potential risk factor for UWCBs.


The Association Between Infants' Attention Control and Social Inhibition is Moderated by Genetic and Environmental Risk for Anxiety.
Infant social inhibition is associated with increased risk for anxiety later in life. Although both genetic and environmental factors are associated with anxiety, little empirical work has addressed how developing regulatory abilities work with genetic and environmental risk to exacerbate or mitigate problem behaviors. The current study was aimed at addressing this gap in research by investigating an early-emerging regulatory behavior, attention control, in association with genetic and environmental risk for anxiety.Participants included 9-month-old adopted infants, their birth mothers, and adoptive parents (n = 361). Lifetime diagnosis of birth mother social phobia was obtained using structured interviews. Adoptive parents completed self-report measures of anxiety symptoms. Infant social inhibition and attention control were coded during a stranger interaction and a barrier task, respectively. Neither adoptive nor birth parent anxiety were directly associated with social inhibition. The association of attention control with social inhibition in infants was moderated by birth and adoptive parent anxiety symptoms. When infants of birth mothers with social phobia were raised by adoptive parents with high self-reported anxiety symptoms, greater attention control was associated with greater social inhibition. However, when raised by adoptive parents with low self-reported anxiety, greater attention control was associated with less social inhibition.


Effects of concentration and volume of 2-chloroprocaine on epidural anesthesia in volunteers.
Effect of local anesthetic concentration and volume on the spread and density of epidural anesthesia is unclear. This study was performed to delineate effects of a threefold difference in concentration and volume of 2-chloroprocaine on epidural anesthesia. Twelve healthy volunteers underwent lumbar epidural anesthesia with 300 mg of 2-chloroprocaine as a 3% (10 ml) and a 1% (30 ml) solution in a randomized, double-blind, balanced, crossover fashion. Sensory block was assessed with pinprick, touch (calibrated plastic filament), cold, and electrical stimulation. Motor block was assessed at the quadriceps and gastrocnemius muscles with isometric force dynamometry. Differences between solutions were assessed with repeated measures analysis of variance followed by post hoc testing. The number of dermatomes blocked to pinprick, touch, and cold was significantly greater with the 1% concentration (2 dermatomes greater than the 3% concentration on average, P < 0.05). Similar intensity of sensory block to electrical stimulation developed at the hip and knee and was unaffected by concentration of 2-chloroprocaine. Similar intensity of motor block developed at the quadriceps with both concentrations. Intensity of sensory and motor block from epidural anesthesia with 2-chloroprocaine appears to depend primarily on total milligram dose.


Assessing Infertility Literacy and Knowledge Gaps Among Patients with Cystic Fibrosis.
As patients with cystic fibrosis live longer into their reproductive years, fertility concerns are rising. We hypothesized that while patients with cystic fibrosis may be informed of the impact of their disease on their reproductive potential, they remain unaware of the promising role of assisted reproductive technology in helping them conceive biological children. We distributed a voluntary and anonymous survey to cystic fibrosis patients and organizations to assess patient understanding of cystic fibrosis-related infertility. The survey questions aimed to capture demographic information, their reproductive education regarding cystic fibrosis, and their preferences for future fertility. Forty respondents completed the survey (median age of 36 ± 14 years). The median age reported for learning about cystic fibrosis-associated infertility was 18 years. Respondents preferred that reproductive and infertility education be provided early; 43% reported the optimal age of education was younger than 18 years while 50% reported between 18 and 24 years. Of the respondents trying to conceive, 43% of patients have been trying to conceive for 1-3 years qualifying for infertility. Yet, the majority of those patients (69%) have not been offered a semen analysis and 90% have not had previous fertility treatments. Our findings highlight that cystic fibrosis patients are knowledgeable about cystic fibrosis-related impacts on their fertility, with high-rated self-confidence. A fraction of patients still desire to conceive but have not been provided with assisted reproductive services. We recommend the establishment of active partnerships between cystic fibrosis care teams and fertility specialists to maximize their chances of conception.


Adversities of acculturation? Prevalence of obesity among immigrants.
I study factors associated with prevalence of obesity among immigrants as the length of their stay in the US becomes longer. Using the National Health Interview Surveys for 1990-2004, I create 'synthetic cohorts' of immigrants that allow controlling for two important determinants of obesity: age at arrival and period of arrival in the US. I find that immigrants with a BA degree did not experience any change in obesity as their stay in the US advanced. Obesity among those without a BA degree, however, increased with duration of stay. Similarly, while some ethnic groups experienced increase in obesity with duration, others did not. For those who experienced increase in obesity with duration, the rise was higher during the first five years of residence than later and greater for those who arrived at a relatively young age.


Deep-water archeology.
There is reason to believe that some old wooden ships on the deep-sea floor have survived for thousands of years without much change. They will not be covered with much sediment, and it will be possible to find them using new searching techniques. These are embodied in the system of the Alcoa Seaprobe, which is also equipped to identify and raise old ships.


Aripiprazole and Other Third-Generation Antipsychotics as a Risk Factor for Impulse Control Disorders: A Systematic Review and Meta-Analysis.
Increasing evidence suggests an association between third-generation antipsychotics (TGAs) and impulse control disorders (ICDs). This is thought to be due to their partial agonism of dopamine receptors. However, neither the relative nor absolute risks of ICDs in those prescribed TGAs are well established. To inform clinical practice, this systematic review and meta-analysis summarizes and quantifies the current evidence for an association. An electronic search of Medline, PsychINFO, EMBASE, and the Cochrane Clinical Trials Database was undertaken from database inception to November 2022. Three reviewers screened abstracts and reviewed full texts for inclusion. A random-effects meta-analysis was conducted with eligible studies. A total of 392 abstracts were retrieved, 214 remained after duplicates were removed. Fifteen full texts were reviewed, of which 8 were included. All 8 studies found that TGAs were associated with increased probability of ICDs. Risk of bias was high or critical in 7 of 8 studies. Three studies were included in the pooled analysis for the primary outcome, 2 with data on each of aripiprazole, cariprazine, and brexpiprazole. Exposure to TGAs versus other antipsychotics was associated with an increase in ICDs (pooled odds ratio, 5.54; 2.24-13.68). Cariprazine and brexpiprazole were significantly associated with ICDs when analyzed individually. Aripiprazole trended toward increased risk, but very wide confidence intervals included no effect. Third-generation antipsychotics were associated with increased risk of ICDs in all studies included and pooled analysis. However, the risk of bias is high, confidence intervals are wide, and the quality of evidence is very low for all TGAs examined.


[PSA kinetics after total prostatectomy].
The prostate specific antigen (PSA) is the best marker of the prostate cancer today although not very specific of this pathology. The dynamic interpretation of this marker always has to prevail over that of overtaking a threshold. With the lack of residual cancer, PSA becomes undetectable by the first month after total prostatectomy: less than 0.1 microg/L. The type of diminution mono- or biphasic of the marker depends on the chronology of the takings. Faced with residual cancer, PSA either does not become undetectable or increases after an initial undetectable period. A recurrence is defined by a value of PSA higher than 0.2 microg/L and confirmed on two successive assays. The time of appearance of the recurrence and the PSA doubling time after total prostatectomy have, with the initial clinical stage and the Gleason score, a diagnostic value on the nature of the site of recurrence, local or metastatic.


A tricycloheptane product in cationic rearrangements.
The bicycloheptene 6 rearranged in acid to give the tricycloheptane 9, as shown by an X-ray crystal structure determination of the p-nitrobenzoate 10 derived from it. Earlier results in the literature had already indicated that this isomer was the thermodynamic sink. This apparently crowded structure, with its three contiguous quaternary centres, is, nevertheless, lower in energy than other accessible but less crowded structures, because of electronic stabilisation of the more substituted cyclopropane ring conjugated to the ester group.


Molecular requirements for recognition of brain voltage-gated sodium channels by scorpion alpha-toxins.
The scorpion alpha-toxin Lqh2 (from Leiurus quinquestriatus hebraeus) is active at various mammalian voltage-gated sodium channels (Na(v)s) and is inactive at insect Na(v)s. To resolve the molecular basis of this preference we used the following strategy: 1) Lqh2 was expressed in recombinant form and key residues important for activity at the rat brain channel rNa(v)1.2a were identified by mutagenesis. These residues form a bipartite functional surface made of a conserved "core domain" (residues of the loops connecting the secondary structure elements of the molecule core), and a variable "NC domain" (five-residue turn and the C-tail) as was reported for other scorpion alpha-toxins. 2) The functional role of the two domains was validated by their stepwise construction on the similar scaffold of the anti-insect toxin LqhalphaIT. Analysis of the activity of the intermediate constructs highlighted the critical role of Phe(15) of the core domain in toxin potency at rNa(v)1.2a, and has suggested that the shape of the NC-domain is important for toxin efficacy. 3) Based on these findings and by comparison with other scorpion alpha-toxins we were able to eliminate the activity of Lqh2 at rNa(v)1.4 (skeletal muscle), hNa(v)1.5 (cardiac), and rNa(v)1.6 channels, with no hindrance of its activity at Na(v)1.1-1.3. These results suggest that by employing a similar approach the design of further target-selective sodium channel modifiers is imminent.


Proteins without unique 3D structures: biotechnological applications of intrinsically unstable/disordered proteins.
Intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs) are functional proteins or regions that do not have unique 3D structures under functional conditions. Therefore, from the viewpoint of their lack of stable 3D structure, IDPs/IDPRs are inherently unstable. As much as structure and function of normal ordered globular proteins are determined by their amino acid sequences, the lack of unique 3D structure in IDPs/IDPRs and their disorder-based functionality are also encoded in the amino acid sequences. Because of their specific sequence features and distinctive conformational behavior, these intrinsically unstable proteins or regions have several applications in biotechnology. This review introduces some of the most characteristic features of IDPs/IDPRs (such as peculiarities of amino acid sequences of these proteins and regions, their major structural features, and peculiar responses to changes in their environment) and describes how these features can be used in the biotechnology, for example for the proteome-wide analysis of the abundance of extended IDPs, for recombinant protein isolation and purification, as polypeptide nanoparticles for drug delivery, as solubilization tools, and as thermally sensitive carriers of active peptides and proteins.


Comparison of conformational changes and inactivation of soybean lipoxygenase-1 during urea denaturation.
The unfolding and inactivation of soybean lipoxygenase-1 during urea denaturation has been compared. Equilibrium study indicates that inactivation of the enzyme occurs at low urea concentrations before significant conformational change of the molecule as a whole. In the presence of 6.0 M urea, the unfolding of soybean lipoxygenase-1, as monitored by fluorescence intensity, is a triphasic process, while the inactivation of the enzyme shows single-phase kinetics. The rate constant of inactivation is consistent with that of the fast conformational change of the enzyme. The results suggest that active sites of lipoxygenase-1 containing iron cofactor are situated in a limited region of the enzyme molecule that is more fragile to denaturants than the protein as a whole. The kinetic theory of substrate reactions catalyzed by unstable enzymes (Duggleby (1986) J. Theor. Biol. 123, 67-80) has been applied to study the effect of substrate on enzyme inactivation. On the basis of the kinetic equation of substrate reaction in the presence of urea, inactivation rate constants for the free enzyme and enzyme-substrate complex have been determined. The substrate, linoleic acid, has no effect on inactivation of the ferric form of lipoxygenase-1.


The Claiming Costs Scale: A new instrument for measuring the costs potential beneficiaries face when claiming social benefits.
It is a well-known feature of social protection systems that not all persons who are entitled to social benefits also claim these benefits. The costs people face when claiming benefits is considered an important cause of this phenomenon of non-take-up. In this paper, we developed and examined the psychometric properties of a new scale, the Claiming Cost Scale (CCS), which measures three dimensions of costs associated with claiming benefits. A multi-phase instrument development method was performed to develop the instrument. The item pool was generated based on a literature review, and presented to academic experts (n = 9) and experts by experience (n = 5) to assess content and face validity. In a second stage, centrality and dispersion, construct validity, convergent and divergent validity, and internal reliability of the instrument were tested. These analyses were based on two samples (n = 141 and n = 1265) of individuals living in low-income households in Belgium. Nine items were retained, which represent three factors (Information costs, Process costs and Stigma). The confirmatory factor analysis proved adequate model fitness. Both convergent and divergent validity were good, and internal consistency was adequate, with Cronbach's alpha ranging between .73 and .87. The findings showed that the CCS is a valid and reliable instrument for assessing the costs potential beneficiaries face when claiming benefits. Consisting of only nine items, the scale can be easily implemented in large-scale survey research or used in day-to-day work of service providers who are interested in understanding non-take-up of their service.


Coronary artery calcium severity grading on non-ECG-gated low-dose chest computed tomography: a multiple-observer study in a nationwide lung cancer screening registry.
To identify the optimal method for evaluation of coronary artery calcium (CAC) severity on non-electrocardiogram-gated low-dose chest computed tomography (LDCT) in a nationwide lung cancer screening registry. A total of 256 subjects were retrospectively enrolled from participants of the Korean Lung Cancer Screening (K-LUCAS) project (an LDCT lung cancer screening registry for high-risk individuals). Four board-certified cardiothoracic radiologists independently assessed CAC severity using four different scoring methods (visual assessment, artery-based grading, segment-involvement grading, and segment-based grading) and classified severity for each case using all four methods as none, mild, moderate, or severe. Agreements between the four observers for CAC category classification and between the four different scoring methods for the same observer were assessed by Fleiss kappa statistics. Evaluation time for CAC grading was compared between observers and between grading methods. Interobserver agreement was moderate for visual assessment (Fleiss kappa 0.451) and substantial for the other three methods (Fleiss kappa 0.673-0.704). Agreement between the four grading methods for the same observer was substantial for three observers (Fleiss kappa 0.610-0.705) and moderate for one (Fleiss kappa 0.578). Mean evaluation time differed significantly between methods (visual assessment, 14.3 ± 11.8 s; artery-based grading, 17.6 ± 22.3 s, segment-involvement grading, 19.2 ± 6.8 s; segment-based grading, 34.2 ± 37.4 s; p < 0.01). Artery-based grading could be appropriate with substantial interobserver agreement and an acceptable mean evaluation time. • CAC severity grading methods on LDCT show moderate to substantial agreements between grading methods and observers. • Artery-based grading could be appropriate with substantial interobserver agreement and a mean evaluation time of 17.6 s. • Visual assessment is disadvantaged by high interobserver variability despite having the shortest evaluation time.


Selected Immunological Mediators and Cervical Microbial Signatures in Women with Chlamydia trachomatis Infection.
In the female genital ecosystem, the complex interplay between the host immune system and the resident microflora protects against urogenital pathogens, like Chlamydia trachomatis C. trachomatis is responsible for urethritis and cervicitis; however, most chlamydial infections are asymptomatic and, thus, not treated, potentially leading to severe reproductive sequelae. Here we investigated the interaction between the levels of selected immune mediators and the community state types of the cervical microbiota in C. trachomatis-infected women. Cervical samples from 42 C. trachomatis-positive women and 103 matched healthy controls were analyzed through the metagenomic analysis of the hypervariable region v4 of the 16S rRNA gene and the determination of lactoferrin, interleukin 1α (IL-1α), IL-6, alpha interferon (IFN-α), IFN-β, and IFN-γ by ELISA. Overall, C. trachomatis infection was significantly associated with a microbiota dominated by anaerobic bacteria (P = 0.000002). In addition, a network of Gardnerella vaginalis, Prevotella amnii, Prevotella buccalis, Prevotella timonensis, Aerococcus christensenii, and Variovorax guangxiensis has been identified as a potential biomarker of C. trachomatis infection through multiple statistical approaches. Again, chlamydial infection was significantly correlated with an increased production of lactoferrin, IL-6, IL-1α, IFN-α, and IFN-β (P < 0.05), whereas very low levels of IFN-γ were observed in C. trachomatis-infected women, levels similar to those detected in healthy women. Our findings show a distinctive signature of C. trachomatis genital infection, characterized by a specific bacterial network, constituted by anaerobes, as well as by increased levels of lactoferrin and proinflammatory cytokines (IL-1α, IL-6, IFN-α, and IFN-β), accompanied by low levels of IFN-γ.IMPORTANCE To our knowledge, this is the first study that investigated the association of C. trachomatis with the cervical levels of lactoferrin and selected inflammatory mediators and their correlation with the different community state types characterizing the female genital ecosystem. C. trachomatis, known as the leading cause of bacterial sexually transmitted diseases, continues to be an important public health problem worldwide for its increasing incidence and the risk of developing severe reproductive sequelae, like pelvic inflammatory disease and infertility. Specifically, C. trachomatis tend to persist in the female genital tract, leading to a chronic inflammatory state characterized by increased production of immune mediators responsible for tissue damage. Therefore, our study may help to broaden the knowledge on the complex interplay between the female genital microbiota and the host immune system in response to C. trachomatis infection.


A time-use study of community health worker service activities in three rural districts of Tanzania (Rufiji, Ulanga and Kilombero).
Despite expanding international commitment to community health worker (CHW) deployment, little is known about how such workers actually use their time. This paper investigates this issue for paid CHWs named "Community Health Agents," which in Swahili is "Wawezeshaji wa Afya ya Jamii" ("WAJA"), trained for 9 months in primary health care service delivery and deployed to villages as subjects of a randomized trial of their impact on childhood survival in three rural districts of Tanzania. To capture information about time allocation, 30 WAJA were observed during conventional working hours by research assistants for 5 days each over a period of 4 weeks. Results were presented in term of percentage time allocation for direct client treatment, documentation activities, health education, health promotion non-work-related activities and personal activities. During routine 8-h workdays, 59.5 % of WAJA time was spent on the provision of health services and other work-related activities. Overall, WAJA spent 27.8 % of their work on traveling from home to home, 33.1 % on health education, 9.9 % of health promotion and only 12.3 % on direct patient care. Other activities related to documentation (7.8 %) and supervision (2.5 %). Results reflect the pressing obligations of WAJA to engage in activities other than direct work responsibilities during routine work hours. Time spent on work activities is primarily used for health education, promotion, moving between households, and direct patient care. However, greater effort should be directed to strengthening supervisory systems and follow-up of challenges WAJAs facing in order to increase proportion of working hours.


2009 Pandemic Influenza A (H1N1): Diagnosis, Management, and Prevention- Lessons Learned.
The 2009 pandemic influenza A (H1N1) was responsible for the first influenza pandemic of the 21st century. The virus- a previously unknown triple-reassortant virus containing segments of avian, human, and swine origins- generally caused mild disease. Unlike seasonal influenza, 2009 pandemic influenza A (H1N1) primarily affected adults 18 to 64 years of age. During the course of the pandemic, public health officials tried to facilitate diagnostic procedures and share information about treatment modalities globally. Efforts to contain the spread of 2009 pandemic influenza A (H1N1) included personal protective mechanisms and the 2009 H1N1 vaccine, which was not produced quickly enough or in large enough quantities. The lessons learned from this pandemic should be applied to ensure better preparedness in case of future pandemics.


Proteomics of the Rat Myocardium during Development of Type 2 Diabetes Mellitus Reveals Progressive Alterations in Major Metabolic Pathways.
Congestive heart failure and poor clinical outcome after myocardial infarction are known complications in patients with type-2 diabetes mellitus (T2DM). Protein alterations may be involved in the mechanisms underlying these disarrays in the diabetic heart. Here we map proteins involved in intracellular metabolic pathways in the Zucker diabetic fatty rat heart as T2DM develops using MS based proteomics. The prediabetic state only induced minor pathway changes, whereas onset and late T2DM caused pronounced perturbations. Two actin-associated proteins, ARPC2 and TPM3, were up-regulated at the prediabetic state indicating increased actin dynamics. All differentially regulated proteins involved in fatty acid metabolism, both peroxisomal and mitochondrial, were up-regulated at late T2DM, whereas enzymes of branched chain amino acid degradation were all down-regulated. At both onset and late T2DM, two members of the serine protease inhibitor superfamily, SERPINA3K and SERPINA3L, were down-regulated. Furthermore, we found alterations in proteins involved in clearance of advanced glycation end-products and lipotoxicity, DCXR and CBR1, at both onset and late T2DM. These proteins deserve elucidation with regard to their role in T2DM pathogenesis and their respective role in the deterioration of the diabetic heart. Data are available via ProteomeXchange with identifiers PXD009538, PXD009554, and PXD009555.


Diffuse idiopathic skeletal hyperostosis in the cervical spine.
The disease processes diffuse idiopathic skeletal hyperostosis, ankylosing spondylitis, and ossification of the posterior longitudinal ligament are similar in pathology and can lead to unexpected but grossly unstable fractures that may not be diagnosed until neurologic change occurs in cases of trivial trauma. A retrospective study of 29 patients with cervical spinal fractures and diffuse idiopathic skeletal hyperostosis-like pathologies was done. Twenty patients with an average age of 62 years were treated surgically (six neurologically complete, five incomplete, nine intact). Three patients with an average age of 70 years died postoperatively (one complete, two incomplete). Nine patients with an average age of 65 years were treated conservatively (five neurologically complete, two incomplete, two intact). All patients with intact neurologic function survived. It is suggested, therefore, that all elderly patients with diffuse idiopathic skeletal hyperostosis-like pathology, history of trivial trauma, and complaint of neck pain be examined carefully for fractures, because mortality rates increase sharply in patients with decreased neurologic function.


The development of thoracic and abdominal muscle depends on SDF1 and CXCR4.
In vertebrates, the lateral body wall muscle formation is thought to be initiated by direct outgrowth of the dermomyotomes resulting in the elongation of the hypaxial myotomes. This contrasts with the formation of the muscles of the girdle, limbs and intrinsic tongue muscles, which originate from long-range migrating progenitors. Previous work shows that the migration of these progenitors requires CXCR4 which is specifically expressed in the migrating cells, but not in the dermomyotome. Here, we show that cells in the ventrolateral-lip (VLL) of the dermomyotome at the flank level express CXCR4 in a pattern consistent with that of Pax3 and MyoR. In ovo gain-of-function experiments using electroporation of SDF-1 constructs into the VLL resulted in increased expression of c-Met, Pax3 and MyoD. In contrast, a loss-of-function approach by implantation of CXCR4-inhibitor beads into the VLL of the flank region caused a reduction in the expression of these markers. These data show that CXCR4 is expressed in the VLL, and by experimentally manipulating the CXCR4/SDF-1 signaling, we demonstrate the importance of this axis in body wall muscle development.


[The usefulness of evaluating effectiveness: pre-implantation genetic screening as an example].
Many treatments are applied in medical practice without a proper evaluation of their effectiveness. In this article, the possible negative consequences of such interventions are illustrated by using pre-implantation genetic screening (PGS) as an example. Research has shown that PGS is both expensive and ineffective. Hypothetically speaking, the non-performance of PGS saved 6 million euro in 2006 and the loss of 369 pregnancies was prevented. The investment in this research was much less than these 6 million euro saved. We postulate making the reimbursement of interventions dependent on their clinical effectiveness, and to use the money saved by this strategy for well-designed and well-executed research on the effectiveness of other interventions.


Spatiotemporal Imaging of Water in Operating Voltage-Gated Ion Channels Reveals the Slow Motion of Interfacial Ions.
Ion channels are responsible for numerous physiological functions ranging from transport to chemical and electrical signaling. Although static ion channel structure has been studied following a structural biology approach, spatiotemporal investigation of the dynamic molecular mechanisms of operational ion channels has not been achieved experimentally. In particular, the role of water remains elusive. Here, we perform label-free spatiotemporal second harmonic (SH) imaging and capacitance measurements of operational voltage-gated alamethicin ion channels in freestanding lipid membranes surrounded by aqueous solution on either side. We observe changes in SH intensity upon channel activation that are traced back to changes in the orientational distribution of water molecules that reorient along the field lines of transported ions. Of the transported ions, a fraction of 10-4 arrives at the hydrated membrane interface, leading to interfacial electrostatic changes on the time scale of a second. The time scale of these interfacial changes is influenced by the density of ion channels and is subject to a crowding mechanism. Ion transport along cell membranes is often associated with the propagation of electrical signals in neurons. As our study shows that this process is taking place over seconds, a more complex mechanism is likely responsible for the propagation of neuronal electrical signals than just the millisecond movement of ions.


Atomoxetine and methylphenidate treatment in children with ADHD: the efficacy, tolerability and effects on executive functions.
The aim of this study was to compare the safety, efficacy, tolerability, and the effects of atomoxetine and OROS-MPH on executive functions in children with ADHD. This study was an open-label study that only included two medication groups. Children were randomized to open-label atomoxetine or OROS-MPH for 12 weeks. Primary efficacy measures were T-DSM-IV-S, CGI-I and neuropsychological tests battery. Safety assessments included electrocardiogram, adverse events checklist and laboratory tests. According to the endpoint improvement scores of CGI and parents T-DSM-IV-S, treatment responses were not significantly different between the two study groups. OROS-MPH led to a significantly greater reduction in teacher T-DSM-IV-S scale scores. OROS-MPH was more effective than atomoxetine on Stroop-5 time and number of corrections. Significant decrease in the percentage of perseverative errors on WCST in the OROS-MPH group was seen (p = 0.005). The most frequently reported adverse events in the atomoxetine group were anorexia, nausea, nervousness, weight loss, abdominal pain, and somnolence. In the OROS-MPH group, patients most frequently reported anorexia, nervousness, insomnia, headache, nausea, and weight loss. When all these results are considered, although both drugs can be considered effective in ADHD treatment, more remarkable improvement is provided by OROS-MPH based on the rates across informant (i.e., teachers, clinicians) and neuropsychological evaluation.


Primary Care and Physical Literacy: A Non-Randomized Controlled Pilot Study to Combat the High Prevalence of Physically Inactive Adults in Austria.
The multidimensional concept of physical literacy is fundamental for lifelong physical activity engagement. However, physical literacy-based interventions are in their infancy, especially among adults. Therefore, the purpose of this pilot study was to assess the association of a physical literacy-based intervention with changes in self-reported physical literacy among inactive adults. A non-randomized controlled study (2 × 2 design) was conducted, comparing pre- vs. postintervention. Twenty-eight inactive healthy participants in the intervention group (89% female, 53 ± 10 years) entered a physical literacy-based intervention once weekly for 14 weeks. The non-treated control group consisted of 22 inactive adults (96% female, 50 ± 11 years). Physical literacy was evaluated with a questionnaire encompassing five domains: physical activity behavior, attitude/understanding, motivation, knowledge, and self-efficacy/confidence. ANOVA models were applied to evaluate changes by time and condition. Following the intervention, significant improvements were seen for overall physical literacy and in four out of five physical literacy domains, including physical activity behavior, attitude/understanding, knowledge, and self-efficacy/confidence (all p < 0.01, Cohen's d = 0.38-0.83). No changes by time x condition were found for motivation. The physical literacy-based intervention applied in this study may be a promising approach to help inactive adults to adopt an active lifestyle.


Statistical learning and children's emergent literacy in rural Côte d'Ivoire.
Studies of non-linguistic statistical learning (SL) have often linked performance in SL tasks with differences in language outcomes. Most of these studies have focused on Western and high-income educational contexts, but children worldwide learn in radically different educational systems and communities, and often in a second language. In the west African nation of Côte d'Ivoire, children enter fifth grade (CM-1) with widely varying ages and literacy skills. Across three iteratively-developed experiments, 157 children, age 8-15 years, in rural communities in the greater-Adzópe region of Côte d'Ivoire watched sequences of cartoon images with embedded triplet patterns on touchscreen tablets, while performing a target-detection task. We assessed these tablet-based adaptations of non-linguistic visual SL and asked whether the children's individual differences in performance on the SL tasks were related to their first and second language and literacy skills. We found group-level evidence that children used the statistical regularities in the image sequence to gradually decrease their response times, but their responses on post-test discrimination did not reflect this learning. When evaluating the correlation between SL and language skills, individual differences related to other task demands predicted oral language skills shared by first and second languages, while SL better predicted second language print skills. These findings suggest that non-linguistic SL paradigms can measure similar skills in Ivorian children as previous samples, but they also echo recent calls for further cross-cultural validation, greater internal reliability, and tests for confounding variables (such as processing speed) in studies of individual differences in statistical learning. RESEARCH HIGHLIGHTS: We iteratively adapted three visual statistical learning studies for children in rural Côte d'Ivoire. Group-level analyses indicates that the children learn the underlying statistical regularities. Individual-differences analyses reveal some evidence that the statistical learning measure is also correlated with task demands that may be driven by cross-cultural differences. Like previous research, statistical learning is correlated with second language literacy, but we did not find a relationship between SL and oral language skills in first and second languages.


Local origins impart conserved bone type-related differences in human osteoblast behaviour.
Osteogenic behaviour of osteoblasts from trabecular, cortical and subchondral bone were examined to determine any bone type-selective differences in samples from both osteoarthritic (OA) and osteoporotic (OP) patients. Cell growth, differentiation; alkaline phosphatase (TNAP) mRNA and activity, Runt-related transcription factor-2 (RUNX2), SP7-transcription factor (SP7), bone sialoprotein-II (BSP-II), osteocalcin/bone gamma-carboxyglutamate (BGLAP), osteoprotegerin (OPG, TNFRSF11B), receptor activator of nuclear factor-κβ ligand (RANKL, TNFSF11) mRNA levels and proangiogenic vascular endothelial growth factor-A (VEGF-A) mRNA and protein release were assessed in osteoblasts from paired humeral head samples from age-matched, human OA/OP (n = 5/4) patients. Initial outgrowth and increase in cell number were significantly faster (p < 0.01) in subchondral and cortical than trabecular osteoblasts, in OA and OP, and this bone type-related differences were conserved despite consistently faster growth in OA. RUNX2/SP7 levels and TNAP mRNA and protein activity were, however, greater in trabecular than subchondral and cortical osteoblasts in OA and OP. BSP-II levels were significantly greater in trabecular and lowest in cortical osteoblasts in both OA and OP. In contrast, BGLAP levels showed divergent bone type-selective behaviour; highest in osteoblasts from subchondral origins in OA and trabecular origins in OP. We found virtually identical bone type-related differences, however, in TNFRSF11B:TNFSF11 in OA and OP, consistent with greater potential for paracrine effects on osteoclasts in trabecular osteoblasts. Subchondral osteoblasts (OA) exhibited highest VEGF-A mRNA levels and release. Our data indicate that human osteoblasts in trabecular, subchondral and cortical bone have inherent, programmed diversity, with specific bone type-related differences in growth, differentiation and pro-angiogenic potential in vitro.


Feasibility of randomised clinical trials in rare diseases: the case of polycythemia vera.
Although it has long been recognised as the only reliable instrument for producing scientific evidence on the benefit/risk profile of therapeutic interventions, the technology of randomised clinical trials (RCT) is far from being the backbone of medical knowledge. Randomised clinical trials in polycythemia vera have been carried out when their methodology was being built up and, therefore, was rather unsatisfactory. Now we have aggressive cytoreductive treatments with chemotherapeutic agents loaded with doubts on long-term safety, while phlebotomy and preventive antiplatelet therapy are left to personal preferences because of debatable results of old, low-power clinical trials. A complex profile of uncertainties requires a simple, but articulated strategy of care and research to allow at the same time a reasonable transfer of the best available validated knowledge and a timely investigation of the most relevant questions. Without doubts, multi-country, collaborative RCTs is the key (not isolated or abstract) element of the current scenario. The declared background hypothesis is the willingness of a medical caring community of being, at the same time and with the same patients, a research community. The trial design comes in as the simplest technical way to deal with uncertainty. Data to be collected, criteria, contents, intensity of follow-up, and documentation of the events are exactly the same as those which are planned and adopted in routine care. One of the greatest achievements of the multicenter trials with this orientation has been to produce a "core" of data and practices, on which the main analyses will be made, but which at the same time reflect an optimal level of assistance to the majority of patients. The purpose of this paper is therefore twofold: a) to provide a brief methodological review of the controlled evidence available for the direction of therapeutic practice for PV: b) to outline and discuss the opportunity, general design, and feasibility of research strategies where a comparative large-scale trial between therapeutic alternatives could play a central role.


Intersexual allometry differences and ontogenetic shifts of coloration patterns in two aquatic turtles, Graptemys oculifera and Graptemys flavimaculata.
Coloration can play critical roles in a species' biology. The allometry of color patterns may be useful for elucidating the evolutionary mechanisms responsible for shaping the traits. We measured characteristics relating to eight aspects of color patterns from Graptemys oculifera and G. flavimaculata to investigate the allometric differences among male, female, and unsexed juvenile specimens. Additionally, we investigated ontogenetic shifts by incorporating the unsexed juveniles into the male and female datasets. In general, male color traits were isometric (i.e., color scaled with body size), while females and juvenile color traits were hypoallometric, growing in size more slowly than the increase in body size. When we included unsexed juveniles in our male and female datasets, our linear regression analyses found all relationships to be hypoallometric and our model selection analysis found support for nonlinear models describing the relationship between body size and color patterns, suggestive of an ontogenetic shift in coloration traits for both sexes at maturity. Although color is critical for many species' biology and therefore under strong selective pressure in many other species, our results are likely explained by an epiphenomenon related to the different selection pressures on body size and growth rates between juveniles and adults and less attributable to the evolution of color patterns themselves.


Examining health care spending trends over a decade: the Palestinian case.
An analysis was made of recent health care spending patterns in the occupied Palestinian territory, in order to inform future health policy-making and planning. Data were obtained from the national health accounts for the period 2000-2011. The current level of resource allocation to the health care sector is higher than in many developed countries and is not sustainable. The private sector represents the largest source of health financing (61%) and the burden falls disproportionally on individual households, who account for 63% of private health care expenditure. Key recommendations include: building capacity in the government sector to reduce the outsourcing of health services; modifying inequitable financing mechanisms to reduce the burden on households; and allocating more resources for health promotion and disease prevention programmes. Reorientation of the health system is also needed in terms of reducing the share of spending on inpatient services in favour of more day surgery, outpatient and home-based services.


Social cognition and work performance of persons with schizophrenia in a Chinese population.
Social-cognitive deficits have a significant impact on the community and vocational functioning of persons with schizophrenia. This study aimed to explore the relationship between social-cognitive abilities and vocational functioning in a Chinese population. We recruited 30 outpatients with schizophrenia to participate. We administered the Chinese Social Cognition and Screening Questionnaire (C-SCSQ) to assess Theory of Mind (ToM), attributional bias, and neurocognition; the Facial Expression Identification Test (FEIT) to assess emotion perception (EP) ability, and the Chinese Work Personality Profile (CWPP) to assess work performance in a simulated work setting. ToM showed a significant negative correlation with attributional bias. The neurocognitive measure displayed a significant positive correlation with ToM and EP. The structural equation model was a good fit to the data (CFI=0.91, RMSEA=0.12), and showed that social-cognitive abilities had a significant impact (-0.41) on work performance. Of the four social-cognitive domains, ToM and paranoid attributional style (PAS) contributed significantly to variations in work performance. These results support the theory that social-cognitive abilities have an impact on work performance. ToM has a positive impact whereas PAS has an adverse effect. Persons with schizophrenia present specific deficits in their social-cognitive abilities, which have significant impact on their work performance and employability.


Mucosal epithelial proliferation of the fallopian tube: a particular association with ovarian serous tumor of low malignant potential?
The presence or absence of tubal mucosal epithelial proliferation (MEP) and its degree of severity when present were investigated in 191 cases, including 49 ovarian serous tumors of low malignant potential (LMP), 33 nonserous (predominantly mucinous) LMP tumors, various other benign and invasive malignant female genital tract lesions, and 37 cases (73 fallopian tubes) of tubal ligation for sterilization. MEP including all degrees of severity was found to be an almost ubiquitous (83% of all cases) lesion of no clinical significance. On the other hand, MEP of moderate or marked degree was rarely seen (3% of cases) in normal tubes obtained for sterilization, but was identified in from 25% to > 40% of tubes accompanying a wide variety of nonneoplastic and neoplastic lesions. Thus, we recommend that only moderate to marked MEP be considered as a diagnosable lesion in the future. There was no tendency in this material for MEP to show any specific association with ovarian serous LMP tumors, as was previously reported. However, when MEP was present, it was more likely to be widespread and mitotically active when it accompanied an ovarian LMP tumor of any histologic type than when it was found with benign ovarian lesions, invasive gynecologic cancers, uterine leiomyomas, or tubal inflammatory lesions and ectopic pregnancies.


Polysaccharides extraction from Opuntia stricta and their protective effect against HepG2 cell death and hypolipidaemic effects on hyperlipidaemia rats induced by high-fat diet.
The aim of this study was to analyse cytoprotective effect of polysaccharides compound from Opuntia stricta (O. stricta) cladode (POS) in vitro including its radical scavenging activities and protective effects against hypercholesterolaemia. Our results showed that glucose was the dominant monosaccharides (30.35%). Arabinose, pyranose, fructose, galactose, glucose, sorbitol, S-inositol, M-inositol, trehalose and saccharose found in this species. O. stricta polysaccharides did not cause any cytotoxic effect on HepG2 cells within the range of concentrations tested (0-400 μgml-1). Pre-treatment of HepG2 cells with POS (100 μgml-1) significantly (p < .05) protected against cytotoxicity induced by DPPH and ABTS radicals. The POS showed strong antioxidant potential in vitro. The results indicated also that POS significantly prevented hypercholesterolaemia-induced elevation of serum biomarkers and induced increase in serum lipid profile. Moreover, the hypercholesterolaemia characterised by elevated lipid peroxidation (MDA) and reduced antioxidant enzyme defences (SOD, CAT and GPx) was restored by POS treatment.


Labeling proteins with small molecules by site-specific posttranslational modification.
We report here the development of a general strategy for site-specific labeling of proteins with small molecules by posttranslational modification enzyme, phosphopantetheinyl transferase Sfp. The target proteins are expressed as fusions to the peptide carrier protein (PCP) excised from nonribosomal peptide synthetase, and Sfp catalyzes the covalent modification of a specific serine residue on PCP by the small molecule-phosphopantetheinyl conjugate. The labeling reaction proceeds with high specificity and efficiency, targeting PCP fusion proteins in the cell lysate. The PCP tag has been shown to be compatible with various proteins, and Sfp-catalyzed PCP modification, compatible with various small-molecule probes conjugated to coenzyme A, highlighting the potential of the PCP tag for site-specific protein labeling with small molecules.


Anticancer Effect of Deuterium Depleted Water - Redox Disbalance Leads to Oxidative Stress.
Despite the convincing empirical evidence that deuterium depleted water (DDW, 25-125 ppm deuterium) has anticancer effect, the molecular mechanism remains unclear. Here, redox proteomics investigation of the DDW action in A549 cells revealed an increased level of oxidative stress, whereas expression proteomics in combination with thermal profiling uncovered crucial role of mitochondrial proteins. In the proposed scenario, reversal of the normally positive deuterium gradient across the inner membrane leads to an increased export of protons from the matrix to intermembrane space and an increase in the mitochondrial membrane potential, enhancing the production of reactive oxygen species (ROS). The resulting oxidative stress leads to slower growth and can induce apoptosis. However, further deuterium depletion in ambient water triggers a feedback mechanism, which leads to restoration of the redox equilibrium and resumed growth. The DDW-induced oxidative stress, verified by traditional biochemical assays, may be helpful as an adjuvant to ROS-inducing anticancer therapy.


Orbitofrontal cortex volume in area 11/13 predicts reward devaluation, but not reversal learning performance, in young and aged monkeys.
The orbitofrontal cortex (OFC) and amygdala are both necessary for decisions based on expected outcomes. Although behavioral and imaging data suggest that these brain regions are affected by advanced age, the extent to which aging alters appetitive processes coordinated by the OFC and the amygdala is unknown. In the current experiment, young and aged bonnet macaques were trained on OFC- and amygdala-dependent tasks that test the degree to which response selection is guided by reward value and can be adapted when expected outcomes change. To assess whether the structural integrity of these regions varies with levels of performance on reward devaluation and object reversal tasks, volumes of areas 11/13 and 14 of the OFC, central/medial (CM), and basolateral (BL) nuclei of the amygdala were determined from high-resolution anatomical MRIs. With age, there were significant reductions in OFC, but not CM and BL, volume. Moreover, the aged monkeys showed impairments in the ability to associate an object with a higher value reward, and to reverse a previously learned association. Interestingly, greater OFC volume of area 11/13, but not 14, was significantly correlated with an animal's ability to anticipate the reward outcome associated with an object, and smaller BL volume was predictive of an animal's tendency to choose a higher value reward, but volume of neither region correlated with reversal learning. Together, these data indicate that OFC volume has an impact on monkeys' ability to guide choice behavior based on reward value but does not impact ability to reverse a previously learned association.


Is pain fatiguing? A structured evidence-based review.
This is a structured, evidence-based review of all available studies on the coexistence of fatigue and pain. To determine what evidence, if any, exists for or against the existence of an association between fatigue and pain and a potential etiological relationship between pain and fatigue. Pain physicians have noted fatigue as a frequent complaint in chronic pain patients (CPPs), and previous studies have reported the association of fatigue and pain. Computer and manual literature searches for studies relating to fatigue and pain produced 23 reports. These references were reviewed in detail, and information relating to the above problems was abstracted and placed into tabular form. Each report was also categorized for the type of study it represented according to the guidelines developed by the Agency for Health Care Policy and Research (AHCPR). In addition, a list of 15 quality criteria was utilized in order to measure the quality of each study. Each study was categorized for each criterion as positive, (criterion filled), negative (criterion not filled), or not applicable independently by two of the authors. A percent quality score was obtained for each study by counting the total number of positives obtained, dividing by 15 minus the total number of not applicable, and multiplying by 100. Only studies having a quality score of 75% or greater were utilized to formulate the conclusions of this review. The strength and consistency of the evidence represented by the remaining studies was then categorized according to the AHCPR guidelines. Conclusions of this review were based on those results. Of the 23 reports, 17 had quality scores of 75% or greater. Of these 17 reports, 94.1% indicated that there was an association between fatigue and pain. In addition, 100% of a subgroup of 13 reports (all with quality scores of 75% or greater) indicated that there may be an etiological relationship between pain and fatigue. The overall strength and consistency of this evidence according to AHCPR guidelines was therefore categorized as A (highly consistent findings from multiple studies). Based on the above results, it was concluded that there is an association between fatigue and pain and that there may be an etiological relationship between pain and fatigue. Pain physicians and other pain treatment professionals should be aware of the high prevalence of fatigue in pain patients. In addition, future research might investigate possible mechanisms for the relationship between pain and fatigue.


Early Prediction of the Need for Orthognathic Surgery in Patients With Repaired Unilateral Cleft Lip and Palate Using Machine Learning and Longitudinal Lateral Cephalometric Analysis Data.
The purpose of this study was to determine the cephalometric predictors of the future need for orthognathic surgery in patients with repaired unilateral cleft lip and palate (UCLP) using machine learning. This study included 56 Korean patients with UCLP, who were treated by a single surgeon and a single orthodontist with the same treatment protocol. Lateral cephalograms were obtained before the commencement of orthodontic/orthopedic treatment (T0; mean age, 6.3 years) and at at least of 15 years of age (T1; mean age, 16.7 years). 38 cephalometric variables were measured. At T1 stage, 3 cephalometric criteria (ANB ≤ -3°; Wits appraisal ≤ -5 mm; Harvold unit difference ≥34 mm for surgery group) were used to classify the subjects into the surgery group (n = 10, 17.9%) and non-surgery group (n = 46, 82.1%). Independent t-test was used for statistical analyses. The Boruta method and XGBoost algorithm were used to determine the cephalometric variables for the prediction model. At T0 stage, 2 variables exhibited a significant intergroup difference (ANB and facial convexity angle [FCA], all P < 0.05). However, 18 cephalometric variables at the T1 stage and 14 variables in the amount of change (ΔT1-T0) exhibited significant intergroup differences (all, more significant than P < 0.05). At T0 stage, the ANB, PP-FH, combination factor, and FCA were selected as predictive parameters with a cross-validation accuracy of 87.4%. It was possible to predict the future need for surgery to correct sagittal skeletal discrepancy in UCLP patients at the age of 6 years.


Stress Signaling in Cyanobacteria: A Mechanistic Overview.
Cyanobacteria are highly diverse, widely distributed photosynthetic bacteria inhabiting various environments ranging from deserts to the cryosphere. Throughout this range of niches, they have to cope with various stresses and kinds of deprivation which threaten their growth and viability. In order to adapt to these stresses and survive, they have developed several global adaptive responses which modulate the patterns of gene expression and the cellular functions at work. Sigma factors, two-component systems, transcriptional regulators and small regulatory RNAs acting either separately or collectively, for example, induce appropriate cyanobacterial stress responses. The aim of this review is to summarize our current knowledge about the diversity of the sensors and regulators involved in the perception and transduction of light, oxidative and thermal stresses, and nutrient starvation responses. The studies discussed here point to the fact that various stresses affecting the photosynthetic capacity are transduced by common mechanisms.


Dose-dependent ATP depletion and cancer cell death following calcium electroporation, relative effect of calcium concentration and electric field strength.
Electroporation, a method for increasing the permeability of membranes to ions and small molecules, is used in the clinic with chemotherapeutic drugs for cancer treatment (electrochemotherapy). Electroporation with calcium causes ATP (adenosine triphosphate) depletion and cancer cell death and could be a novel cancer treatment. This study aims at understanding the relationship between applied electric field, calcium concentration, ATP depletion and efficacy. In three human cell lines--H69 (small-cell lung cancer), SW780 (bladder cancer), and U937 (leukaemia), viability was determined after treatment with 1, 3, or 5 mM calcium and eight 99 μs pulses with 0.8, 1.0, 1.2, 1.4 or 1.6 kV/cm. Fitting analysis was applied to quantify the cell-killing efficacy in presence of calcium. Post-treatment intracellular ATP was measured in H69 and SW780 cells. Post-treatment intracellular ATP was observed with fluorescence confocal microscopy of quinacrine-labelled U937 cells. Both H69 and SW780 cells showed dose-dependent (calcium concentration and electric field) decrease in intracellular ATP (p<0.05) and reduced viability. The 50% effective cell kill was found at 3.71 kV/cm (H69) and 3.28 kV/cm (SW780), reduced to 1.40 and 1.15 kV/cm (respectively) with 1 mM calcium (lower EC50 for higher calcium concentrations). Quinacrine fluorescence intensity of calcium-electroporated U937 cells was one third lower than in controls (p<0.0001). Calcium electroporation dose-dependently reduced cell survival and intracellular ATP. Increasing extracellular calcium allows the use of a lower electric field. This study supports the use of calcium electroporation for treatment of cancer and possibly lowering the applied electric field in future trials.


Comparative performance of three metabolic syndrome definitions in the prediction of acute coronary syndrome.
The value of the recently introduced definitions of metabolic syndrome (MetS) in the identification of high cardiovascular risk subjects remains questionable. We examined the association among different definitions of MetS, and the occurrence of a first-ever acute coronary syndrome (ACS). We studied 211 patients with a first-ever ACS and 210 control subjects. We recorded cardiovascular risk factors and the presence of MetS using 3 different definitions, according to the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP) III, National Heart, Lung and Blood Institute/American Heart Association (NHLBI/AHA), and International Diabetes Federation (IDF), respectively. The association of MetS with ACS was assessed using univariate and multivariate logistic regression models after adjusting for potential confounding factors, such as gender, age, body mass index, hypertension, diabetes mellitus, and lipids. ACS cases had a prevalence of metabolic syndrome according to NCEP-ATP III, NHLBI/AHA, and IDF criteria of 72.5%, 81.2%, and 79.1%, respectively. The unadjusted odds ratio (OR) for a first-ever ACS were 2.32 (95% CI: 1.53-3.52, p=0.001), 2.82 (95% CI: 1.79-4.43, p=0.001), and 3.26 (95% CI: 2.12-5.00, p=0.001) for NCEP-ATP III, NHLBI/AHA, and IDF MetS definitions, respectively. Multivariate analyses revealed that only IDF-defined MetS was significantly associated with ACS (OR: 2.23 95% CI: 1.30-3.82, p=0.003), while of the MetS components only waist circumference remained independently associated with ACS (O.R: 1.045 95% CI: 1.014-1.078, p=0.005). The definition of MetS according to the IDF criteria appears to be a better predictor of ACS than NCEP-ATP III and NHLBI/AHA.


Ultrafast laser photoinscription of polarization sensitive devices in bulk silica glass.
Ultrashort pulsed laser irradiation of bulk fused silica may result under specific energetic conditions in the self-organization of subwavelength material redistribution regions within the laser trace. The modulated structures have birefringent properties and show unusual anisotropic light scattering and reflection characteristics. We report here on the formation of waveguiding structures with remarkable polarization effects for infrared light. The photoinscription process using 800 nm femtosecond laser pulses is accompanied by third harmonic generation and polarization dependent anisotropic scattering of UV photons. The photowritten structures can be arranged in three-dimensional patterns generating complex propagation and polarization effects due to the anisotropic optical properties.


Molecular Dynamics and Physical Stability of Ibuprofen in Binary Mixtures with an Acetylated Derivative of Maltose.
In this paper, we explore the strategy increasingly used to improve the bioavailability of poorly water-soluble crystalline drugs by formulating their amorphous solid dispersions. We focus on the potential application of a low molecular weight excipient octaacetyl-maltose (acMAL) to prepare physically stable amorphous solid dispersions with ibuprofen (IBU) aimed at enhancing water solubility of the drug compared to that of its crystalline counterpart. We thoroughly investigate global and local molecular dynamics, thermal properties, and physical stability of the IBU+acMAL binary systems by using broadband dielectric spectroscopy and differential scanning calorimetry as well as test their water solubility and dissolution rate. The obtained results are extensively discussed by analyzing several factors considered to affect the physical stability of amorphous systems, including those related to the global mobility, such as plasticization/antiplasticization effects, the activation energy, fragility parameter, and the number of dynamically correlated molecules as well as specific intermolecular interactions like hydrogen bonds, supporting the latter by density functional theory calculations. The observations made for the IBU+acMAL binary systems and drawn recommendations give a better insight into our understanding of molecular mechanisms governing the physical stability of amorphous solid dispersions.


The impact of work-limiting disability on labor force participation.
According to the justification hypothesis, non-employed individuals may over-report their level of work limitation, leading to biased census/survey estimates of the prevalence of severe disabilities and the associated labor force participation rate. For researchers studying policies which impact the disabled or elderly (e.g., Supplemental Security Income, Disability Insurance, and Early Retirement), this could lead to significant bias in key parameters of interest. Using the American Community Survey, we examine the potential for both inflated and deflated reported disability status and generate a general index of disability, which can be used to reduce the bias of these self-reports in other studies. We find that at least 4.8 million individuals have left the labor force because of a work-limiting disability, at least four times greater than the impact implied by our replication of previous models.


T1ρ-based fibril-reinforced poroviscoelastic constitutive relation of human articular cartilage using inverse finite element technology.
Mapping of T1ρ relaxation time is a quantitative magnetic resonance (MR) method and is frequently used for analyzing microstructural and compositional changes in cartilage tissues. However, there is still a lack of study investigating the link between T1ρ relaxation time and a feasible constitutive relation of cartilage which can be used to model complicated mechanical behaviors of cartilage accurately and properly. Three-dimensional finite element (FE) models of ten in vitro human tibial cartilage samples were reconstructed such that each element was assigned by material-level parameters, which were determined by a corresponding T1ρ value from MR maps. A T1ρ-based fibril-reinforced poroviscoelastic (FRPE) constitutive relation for human cartilage was developed through an inverse FE optimization technique between the experimental and simulated indentations. A two-parameter exponential relationship was obtained between the T1ρ and the volume fraction of the hydrated solid matrix in the T1ρ-based FRPE constitutive relation. Compared with the common FRPE constitutive relation (i.e., without T1ρ), the T1ρ-based FRPE constitutive relation indicated similar indentation depth results but revealed some different local changes of the stress distribution in cartilages. Our results suggested that the T1ρ-based FRPE constitutive relation may improve the detection of changes in the heterogeneous, anisotropic, and nonlinear mechanical properties of human cartilage tissues associated with joint pathologies such as osteoarthritis (OA). Incorporating T1ρ relaxation time will provide a more precise assessment of human cartilage based on the individual in vivo MR quantification.


Engaging Native American Caregivers in Youth-Focused Diabetes Prevention and Management.
Native American youth aged 10 to 19 years are disproportionately affected by type 2 diabetes. Intergenerational programs may improve health in tribal communities. We evaluated Together on Diabetes, a diabetes prevention and management program, among 257 participating Native American youths with or at risk for type 2 diabetes and their adult caregivers. Feasibility, acceptability, and demographic data were collected from 226 adult caregivers. Data on physical measurements (weight, height, waist circumference) were collected from 37 of the caregivers. Results indicated that engaging adult caregivers was feasible, acceptable, and effective. Furthermore, a subset of adult caregivers reduced their body mass index (weight in kilograms divided by height in m2) significantly from the start to the end of the program, a 12 month period (P = .02). Findings suggest the feasibility of engaging adult caregivers in youth diabetes prevention programs.


Results of treatment of 145 fractures of the third metacarpal/metatarsal condyles in 135 horses (1986-1994).
The objectives of this study were to correlate condylar fracture characteristics and type of treatment with subsequent capacity for athletic ability, and to determine the characteristics of healing that affect prognosis after fracture fixation. Medical records, post operative radiographic studies and race records were examined for 135 horses sustaining 145 fractures. Sixty-five percent of horses overall started in a race post injury (SPI) in a mean time of 9.7 months with a mean of 13.7 races post injury. Having raced pre-injury did not confer an advantage to starting post injury, though nonstarters pre-injury tended to take longer to return. For horses starting pre- and post injury, 66% improved or maintained their race class level after injury, whereas 64.2% decreased their race earnings post injury. Eighty-five percent of the fractures received internal fixation, of which 70% were complete fractures. Eighty-seven percent of horses with incomplete-nondisplaced fractures treated conservatively raced post injury. The percent SPI for incomplete-nondisplaced, complete-nondisplaced and complete-displaced fractures treated with internal fixation were 74%, 58%, and 60%, respectively. Males (72%) raced post injury more frequently than fillies (53%), and may represent a truer probability of SPI. Spiral fractures tended to take longer until their first start (mean 13.3 months). Fifty-two percent of horses with articular fragments were able to race post injury. Horses were more likely to start if 2-4 month radiographic healing revealed no evidence of the fracture except the presence of lag screws. Based on this series of cases, the majority of horses, with proper treatment, were able to return to racing regardless of fracture characteristic. Prognosis appeared to be affected by the severity of the injury to the joint, the presence of articular comminution and the quality of surgical repair.


Identification of the zebrafish ventral habenula as a homolog of the mammalian lateral habenula.
The mammalian habenula consists of the medial and lateral habenulae. Recent behavioral and electrophysiological studies suggested that the lateral habenula plays a pivotal role in controlling motor and cognitive behaviors by influencing the activity of dopaminergic and serotonergic neurons. Despite the functional significance, manipulating neural activity in this pathway remains difficult because of the absence of a genetically accessible animal model such as zebrafish. To address the level of lateral habenula conservation in zebrafish, we applied the tract-tracing technique to GFP (green fluorescent protein)-expressing transgenic zebrafish to identify habenular neurons that project to the raphe nuclei, a major target of the mammalian lateral habenula. Axonal tracing in live and fixed fish showed projection of zebrafish ventral habenula axons to the ventral part of the median raphe, but not to the interpeduncular nucleus where the dorsal habenula projected. The ventral habenula expressed protocadherin 10a, a specific marker of the rat lateral habenula, whereas the dorsal habenula showed no such expression. Gene expression analyses revealed that the ventromedially positioned ventral habenula in the adult originated from the region of primordium lateral to the dorsal habenula during development. This suggested that zebrafish habenulae emerge during development with mediolateral orientation similar to that of the mammalian medial and lateral habenulae. These findings indicated that the lateral habenular pathways are evolutionarily conserved pathways and might control adaptive behaviors in vertebrates through the regulation of monoaminergic activities.


Sum frequency generation and solid-state NMR study of the structure, orientation, and dynamics of polystyrene-adsorbed peptides.
The power of combining sum frequency generation (SFG) vibrational spectroscopy and solid-state nuclear magnetic resonance (ssNMR) spectroscopy to quantify, with site specificity and atomic resolution, the orientation and dynamics of side chains in synthetic model peptides adsorbed onto polystyrene (PS) surfaces is demonstrated in this study. Although isotopic labeling has long been used in ssNMR studies to site-specifically probe the structure and dynamics of biomolecules, the potential of SFG to probe side chain orientation in isotopically labeled surface-adsorbed peptides and proteins remains largely unexplored. The 14 amino acid leucine-lysine peptide studied in this work is known to form an alpha-helical secondary structure at liquid-solid interfaces. Selective, individual deuteration of the isopropyl group in each leucine residue was used to probe the orientation and dynamics of each individual leucine side chain of LKalpha14 adsorbed onto PS. The selective isotopic labeling methods allowed SFG analysis to determine the orientations of individual side chains in adsorbed peptides. Side chain dynamics were obtained by fitting the deuterium ssNMR line shape to specific motional models. Through the combined use of SFG and ssNMR, the dynamic trends observed for individual side chains by ssNMR have been correlated with side chain orientation relative to the PS surface as determined by SFG. This combination provides a more complete and quantitative picture of the structure, orientation, and dynamics of these surface-adsorbed peptides than could be obtained if either technique were used separately.


STUDIES ON ISOLATED CELL COMPONENTS. XVI. THE DISTRIBUTION OF ACID PHENYL PHOSPHATASE ACTIVITIES IN RAT LIVER BREI FRACTIONATED IN THE ZONAL ULTRACENTRIFUGE.
The zonal ultracentrifuge has been used to separate the major components of rat liver brei (soluble phase, ribosomes, microsomes, mitochondria, membranous fragments, and nuclei) during one centrifugation, by using a 1200 ml sucrose gradient varying linearly with radius from 17 to 55 per cent (w/w) with a "cushion" of 66 per cent sucrose at the rotor edge at speeds up to 30,000 RPM. Liver brei was found to contain a family of phosphatases (phenol disodium phosphate substrate, sodium malonate buffers and Turgitol NPX, a non-ionic detergent). Activity maxima at pH 4.1 and 5.9 were observed in untreated brei prepared in 0.25 M sucrose. The addition of the non-ionic detergent Turgitol NPX selectively caused the release of considerable additional activity between these optima. The activity measured at pH 4.1 was primarily associated with the cytoplasmic granules, while the activities at pH 4.8, 5.4 and 5.9 were found in both soluble phase and particulate-mitochondria and membranous fractions. The activities present beyond the region of the gradient occupied by the soluble phase (sample layer) were all bound to particles sedimentable at 105,536 g (average) in the preparative ultracentrifuge. The data suggest that the different activities are not similarly distributed between soluble phase and particulate fractions. When the data are expressed in terms of specific activity, the area in the gradient between the microsomes and mitochondria now appears richest in all the acid phenyl phosphatase activities measured, while the soluble phase and larger particulate fractions appear relatively poor in activity. This part of the gradient is occupied by small, dense granules which may be the so called lysosomes. Pretreatment of the brei with Turgitol NPX prior to fractionation in the zonal ultracentrifuge resulted in the solubilization of acid phenyl phosphatase activities (almost all the activity was in the sample zone of the gradient) and the non-specific destruction of the formed elements of the brei. Essentially all of the activities present in the original brei measured under these conditions were recovered after zonal ultracentrifuge fractionations.


The effects of calcium phosphate cement particles on osteoblast functions.
Calcium phosphate cements (CPC) are increasingly used in the orthopedic field. This kind of cement has potential applications in bone defect replacements, osteosynthetic screw reinforcements or drug delivery. In vivo studies have demonstrated a good osteointegration of CPC. However, it was also observed that the resorption of CPC could create particles. It is known from orthopedic implant studies that particles can be responsible for the peri-implant osteolysis. Biocompatibility assessment of CPC should then be performed with particles. In this study, we quantified the functions of osteoblasts in the presence of beta-TCP, brushite and cement particles. Two particle sizes were prepared. The first one corresponded to the critical diameter range 1-10 microm and the second one had a diameter larger than 10 microm. We found that CPC particles could adversely affect the osteoblast functions. A decrease in viability, proliferation and production of extracellular matrix was measured. A dose effect was also observed. A ratio of 50 CPC particles per osteoblast could be considered as the maximum number of particles supported by an osteoblast. The smaller particles had stronger negative effects on osteoblast functions than the larger ones. Future CPC development should minimize the generation of particles smaller than 10 microm.


What radiation dose for DLA-identical canine marrow grafts?
In view of reported attempts at marrow grafting after nuclear accidents with a broad range of radiation exposures, the present study explored the total-body irradiation (TBI) conditions needed for engraftment in a canine model by using marrow from DLA-identical littermates. Previous studies have shown that such grafts are consistently successful when recipients are exposed to 920 cGy of TBI delivered at a rate of 7 cGy/min from opposing dual cobalt sources. The present TBI doses were all in the lethal range. Five dogs were administered 450 cGy; seven dogs, 600 cGy; five dogs, 700 cGy; and five dogs, 800 cGy of TBI administered at 7 cGy/min. They received a median of 3.3 x 10(8) marrow cells/kg intravenously after completion of radiation. Results showed transient allogeneic marrow engraftment in all dogs administered the lowest dose of TBI studied (450 cGy). Importantly, transient grafts permitted four of five dogs to live long enough for autologous marrow recovery to occur. At increasing radiation doses, 600, 700, and 800 cGy, the risk of graft failure lessened, with 3 of 7, 2 of 5, and 1 of 5 dogs, respectively, showing graft rejection. Fewer dogs survived with autologous marrow recovery, and more showed sustained allogeneic engraftment (4 of 7, 3 of 5, and 4 of 5 dogs, respectively). We conclude that DLA-identical littermate marrow grafts are beneficial in the setting of otherwise lethal radiation exposures, with most dogs either experiencing sustained allogeneic engraftment or surviving with autologous marrow recovery due to the extended support provided by a transient allogeneic graft.


Hepatic lipocalin 2 promotes liver fibrosis and portal hypertension.
Advanced fibrosis and portal hypertension influence short-term mortality. Lipocalin 2 (LCN2) regulates infection response and increases in liver injury. We explored the role of intrahepatic LCN2 in human alcoholic hepatitis (AH) with advanced fibrosis and portal hypertension and in experimental mouse fibrosis. We found hepatic LCN2 expression and serum LCN2 level markedly increased and correlated with disease severity and portal hypertension in patients with AH. In control human livers, LCN2 expressed exclusively in mononuclear cells, while its expression was markedly induced in AH livers, not only in mononuclear cells but also notably in hepatocytes. Lcn2-/- mice were protected from liver fibrosis caused by either ethanol or CCl4 exposure. Microarray analysis revealed downregulation of matrisome, cell cycle and immune related gene sets in Lcn2-/- mice exposed to CCl4, along with decrease in Timp1 and Edn1 expression. Hepatic expression of COL1A1, TIMP1 and key EDN1 system components were elevated in AH patients and correlated with hepatic LCN2 expression. In vitro, recombinant LCN2 induced COL1A1 expression. Overexpression of LCN2 increased HIF1A that in turn mediated EDN1 upregulation. LCN2 contributes to liver fibrosis and portal hypertension in AH and could represent a new therapeutic target.


Comparison of a Dental Operating Microscope and High-resolution Videoscope for Endodontic Procedures.
The purpose of this study was to compare a dental operating microscope (DOM) with a high-resolution videoscope (VS) in terms of depth of field (DOF), resolution, and effect on fine motor skills. Two observers used test targets to measure the resolution and DOF of the DOM and the VS. In addition, 18 participants (12 dental students and 6 endodontic residents) performed an accuracy test on a manikin head using DOM, VS, or loupes. Each participant completed a posttest survey. The 3 magnifications of the DOM had higher resolutions and DOF (resolution: 32, 40.3, and 50.8 line pairs/mm; DOF: 15, 10, and 6 mm) than the VS (resolution: 20.1 line pairs/mm; DOF: 5 mm). Accuracy testing showed the DOM produced better results than the VS for both resident and student groups (P < .001); however, the VS was not significantly different than loupes. The residents performed better than the students using the DOM and the VS (P < .001). The students in general took 1.3 times longer than the residents to perform the accuracy test, irrespective of the magnification device used. The DOM and the VS required on average 1.9 and 2.8 times longer compared with loupes, respectively. Most participants reported a preference for the DOM with regard to visualization and ease of use. Comments also suggested that the VS has value in diagnosis and magnification in endodontics. Considering the findings from this study, the DOM stands out as the leading magnification tool in endodontics. However, the VS has potential in endodontic procedures and might be used as an adjunct to other visualization aids.


Significance of Data Selection in Deep Learning for Reliable Binding Mode Prediction of Ligands in the Active Site of CYP3A4.
For rational drug design, it is essential to predict the binding mode of protein-ligand complexes. Although various machine learning-based models have been reported that use convolutional neural networks (deep learning) to predict binding modes from three-dimensional structures, there are few detailed reports on how best to construct and use datasets. Here, we examined how different datasets affected the prediction of the binding mode of CYP3A4 by a three-dimensional neural network when the number of crystal structures for the target protein was limited. We used four different training datasets: one large, general dataset containing various protein complexes and three smaller, more specific datasets containing complexes with CYP3A4-like pockets, complexes with CYP3A4-binding ligands, and complexes with CYP protein family members. We then trained models with different combinations of datasets with or without subsequent fine-tuning and evaluated the binding mode prediction performance of each model. The best receiver operating characteristic (ROC) area under the curve (AUC) model with respect to area under the receiver operating characteristic curve was obtained by training with a combination of the general protein and CYP family datasets. However, the ROC AUC-recall balanced model was obtained by training with this combination of datasets followed by fine-tuning with the CYP3A4-binding ligands dataset. Our results suggest that datasets that balance protein functionality and data size are important for optimizing binding mode prediction performance. In addition, datasets with large median binding pocket sizes may be important for the binding mode prediction specifically of CYP3A4.


Dissociation of body growth and adipose deposition effects of growth hormone in oMt1a-oGH transgenic mice.
Chronic highly elevated expression of a growth hormone (GH) transgene enhances overall body growth with minimal adipose accretion, while moderate levels of circulating GH fail to enhance body growth yet promote adipose deposition. These findings suggest that the growth response to GH can be dissociated from adipose effects. This hypothesis was tested in the oMtla-oGH transgenic mouse model by titrating circulating GH levels through variable induction of transgene expression. Circulating GH levels in female transgenics were approximately 49, 132, and 750 ng/ml in response to the transgene stimulus at 0, 15, and 25 mM zinc sulfate, respectively. The highest level of circulating GH generated the largest body weight with the smallest fat accrual while the intermediate GH level generated a body weight equivalent to that for the highest GH but the heaviest gonadal fat pads. The lowest GH levels did not increase body size but did enlarge fat depots. Animals exposed to the highest level of GH had an extended growth phase relative to lower GH levels and the nontransgenic controls. In contrast, the duration of the growth phase for the 0 and 15 mM zinc stimulated transgenics was abbreviated relative to the growth phase of the control animals. The two highest levels of circulating GH increased all forms of the GH receptor, IGF-I, and hepatic lipoprotein lipase mRNA. The growth differential observed for the 0 vs. the 15 mM zinc stimulated transgenics may reflect the preferential increase in the full length GH receptor mRNA and the induction of the smaller IGF-I transcripts with the higher circulating GH while the lipid accrual paralleled the disproportionate induction of the truncated GH receptor mRNA form. Liver and bone content of zinc, manganese, copper, and iron primarily reflected dietary zinc supplementation and did not appear to play a role in the differential growth response. The dissociation of GH effects on growth and adipogenesis as a function of circulating GH levels suggests that the level of GHR and IGF-I expression acts through a threshold mechanism and low expression results in adipogenesis while high expression generates body growth.


A Comprehensive Infrastructure for Big Data in Cancer Research: Accelerating Cancer Research and Precision Medicine.
Advancements in next-generation sequencing and other -omics technologies are accelerating the detailed molecular characterization of individual patient tumors, and driving the evolution of precision medicine. Cancer is no longer considered a single disease, but rather, a diverse array of diseases wherein each patient has a unique collection of germline variants and somatic mutations. Molecular profiling of patient-derived samples has led to a data explosion that could help us understand the contributions of environment and germline to risk, therapeutic response, and outcome. To maximize the value of these data, an interdisciplinary approach is paramount. The National Cancer Institute (NCI) has initiated multiple projects to characterize tumor samples using multi-omic approaches. These projects harness the expertise of clinicians, biologists, computer scientists, and software engineers to investigate cancer biology and therapeutic response in multidisciplinary teams. Petabytes of cancer genomic, transcriptomic, epigenomic, proteomic, and imaging data have been generated by these projects. To address the data analysis challenges associated with these large datasets, the NCI has sponsored the development of the Genomic Data Commons (GDC) and three Cloud Resources. The GDC ensures data and metadata quality, ingests and harmonizes genomic data, and securely redistributes the data. During its pilot phase, the Cloud Resources tested multiple cloud-based approaches for enhancing data access, collaboration, computational scalability, resource democratization, and reproducibility. These NCI-led efforts are continuously being refined to better support open data practices and precision oncology, and to serve as building blocks of the NCI Cancer Research Data Commons.