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Raimunda Sheyla Carneiro Dias,1 Dyego José de Araújo Brito,1 Elisângela Milhomem dos Santos,2 Rayanna Cadilhe de Oliveira Costa,1 Andrea Martins Melo Fontenele,1 Elane Viana Hortegal Furtado,1 Joyce Santos Lages,1 Alcione Miranda dos Santos,3 Elton Jonh Freitas Santos,1 Érika Cristina Ribeiro de Lima Carneiro,1 Maria Célia Cruz Diniz,1 Carla Déa Trindade Barbosa,1 Alessandra Costa de Sales Muniz,1 Ana Karina Teixeira da Cunha França,3 Natalino Salgado Filho,4 Denizar Vianna Araújo,5 Mário Bernardo-Filho6 1Center for Prevention of Kidney Diseases, University Hospital of the Federal University of Maranhão, São Luís, MA, Brazil; 2Nursing Department, Federal University of Maranhão, São Luís, MA, Brazil; 3Public Health Department, Federal University of Maranhão, São Luís, MA, Brazil; 4Department of Medicine I, Federal University of Maranhão, São Luís, MA, Brazil; 5Department of Internal Medicine, University of the State of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; 6Laboratory of Mechanical Vibrations and Integrative Practices, Department of Biophysics and Biometrics, Institute of Biology Roberto Alcântara Gomes and Polyclinic Américo Piquet Carneiro, University of the State of Rio de Janeiro, Rio de Janeiro, RJ, BrazilCorrespondence: Raimunda Sheyla Carneiro Dias Tel +55 98 981545296Email sheylak75@yahoo.com.brBackground: Disorders of mineral metabolism occur in most patients with chronic kidney disease (CKD). The aim of this work was to correlate parathyroid hormone (PTH) levels with urinary magnesium excretion in patients with non-dialysis dependent CKD.Methods: Cross-sectional study. Concentrations of creatinine, magnesium, calcium, phosphate, parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH)D] and alkaline phosphatase (ALP) were determined in blood samples. The assessment of urinary magnesium levels was performed by means of total daily excretion and by the excretion fraction (FEMg).Results: The study evaluated 163 patients with a mean age of 60.7 ± 11.7 years and 51.0% were male. In the highest quartile of PTH (> 89.5pg/mL), the mean levels of FEMg and ALP were higher (p< 0.05). In the unadjusted regression analysis, the following variables were related to serum PTH levels: FEMg (odds ratio (OR) = 1.12; 95% confidence intervals (CI): 1.02– 1.23), calcium (OR = 0.45; 95% CI: 0.22– 0.90), ALP (OR = 1.02; 95% CI: 1.00– 1.03) and eGFR (OR = 0.92; 95% CI: 1.00– 1.03). After an adjusted analysis, only one FEMg and ALP will remain correlated with PTH.Conclusion: In patients with non-dialysis dependent CKD, FEMg and ALP were some variables that remained associated with PTH.Keywords: magnesium, parathyroid hormone, kidney diseases

Elton Jonh Freitas Santos,1 Raimunda Sheyla Carneiro Dias,1 Janielle Ferreira de Brito Lima,1 Natalino Salgado Filho,2 Alcione Miranda dos Santos2 1University Hospital of the Federal University of Maranhão, São Luís, Brazil; 2Federal University of Maranhão, São Luís, BrazilCorrespondence: Elton Jonh Freitas SantosUniversity Hospital of the Federal University of Maranhão, Rua Barão de Itapary – 227, Centro, São Luís CEP 65020-070, MA, BrazilTel +98 2109.1089/2109.1024Email eltonfreitas86@yahoo.com.brAbstract: Anemia is a frequent complication of chronic kidney disease, and its primary cause is erythropoietin deficiency. After diagnosis, treatment begins with administration of an erythropoiesis-stimulating agent (ESA). However, some patients present with resistance to ESA, which needs to be reversed, as it can increase the risk of death in patients with kidney disease. Therefore, we provide a discussion of the current literature regarding the factors that can modify the response to this class of drugs and the strategies that can be considered to optimize the benefits of treating anemia.Keywords: anemia, chronic kidney disease, erythropoietin, drug resistance

Low-efficacy mu opioid receptor (MOR) agonists may serve as novel candidate analgesics with improved safety relative to high-efficacy opioids. This study used a recently validated assay of pain-depressed behavior in mice to evaluate a novel series of MOR-selective C9-substituted phenylmorphan opioids with graded MOR efficacies. Intraperitoneal injection of dilute lactic acid (IP acid) served as a noxious stimulus to depress locomotor activity by mice in an activity chamber composed of two compartments connected by an obstructed door. Behavioral measures included (1) crosses between compartments (vertical activity over the obstruction) and (2) movement counts quantified as photobeam breaks summed across compartments (horizontal activity). Each drug was tested alone and as a pretreatment to IP acid. A charcoal-meal test and whole-body-plethysmography assessment of breathing in 5% CO 2 were also used to assess gastrointestinal (GI) inhibition and respiratory depression, respectively. IP acid produced a concentration-dependent depression in crosses and movement that was optimally alleviated by intermediate- to low-efficacy phenylmorphans with sufficient efficacy to produce analgesia with minimal locomotor disruption. Follow-up studies with two low-efficacy phenylmorphans (JL-2-39 and DC-1-76.1) indicated that both drugs produced naltrexone-reversible antinociception with a rapid onset and a duration of ∼1 h. Potency of both drugs increased when behavior was depressed by a lower IP-acid concentration, and neither drug alleviated behavioral depression by a non-pain stimulus (IP lithium chloride). Both drugs produced weaker GI inhibition and respiratory depression than fentanyl and attenuated fentanyl-induced GI inhibition and respiratory depression. Results support further consideration of selective, low-efficacy MOR agonists as candidate analgesics. SIGNIFICANCE STATEMENT: This study used a novel set of mu opioid receptor (MOR)-selective opioids with graded MOR efficacies to examine the lower boundary of MOR efficacy sufficient to relieve pain-related behavioral depression in mice. Two novel low-efficacy opioids (JL-2-39, DC-1-76.1) produced effective antinociception with improved safety relative to higher- or lower-efficacy opioids, and results support further consideration of these and other low-efficacy opioids as candidate analgesics., (U.S. Government work not protected by U.S. copyright.)

Treatment of peri-implant diseases focuses on reducing the bacterial load and consequent infection control. The use of local antimicrobials as an adjunct to mechanical therapy may result in a better outcome. Among antimicrobials, doxycycline stands out because of its local modulation of cytokines, microbial reduction, and clinical parameters in the treatment of periodontal diseases. The objective of this case report was to describe the combined application of mechanical debridement and bioresorbable doxycycline-loaded nanospheres for the treatment of peri-implantitis in a 71-year-old man. At the 3-year evaluation, the peri-implant tissues had improved, showing decreased probing depths, an absence of bleeding on probing, and no suppuration. This case report highlights the importance of supportive therapy, which is essential for the long-term success of peri-implantitis treatment., Competing Interests: No conflicts of interest reported.

The allele frequency net database (AFND, http://www.allelefrequencies.net ) is an online web-based repository that contains information on the frequencies of immune-related genes and their corresponding alleles in worldwide human populations. At present, the website contains data from 1784 population samples in more than 14 million individuals from 129 countries on the frequency of genes from different polymorphic regions including data for the human leukocyte antigen (HLA) system. In addition, over the last four years, AFND has also incorporated genotype raw data from 85,000 individuals comprising 215 population samples from 39 countries. Moreover, more population data sets containing next generation sequencing data spanning >3 million individuals have been added. This resource has been widely used in a variety of contexts such as histocompatibility, immunology, epidemiology, pharmacogenetics, epitope prediction algorithms for population coverage in vaccine development, population genetics, among many others. In this chapter, we present an update of the most used searching mechanisms as described in a previous volume and some of the latest developments included in AFND., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Elevated fibroblast growth factor 23 (FGF23) in X-linked hypophosphatemia (XLH) results in rickets and phosphate wasting, manifesting by severe bone and dental abnormalities. Burosumab, a FGF23-neutralizing antibody, an alternative to conventional treatment (phosphorus and active vitamin D analogs), showed significant improvement in the long bone phenotype. Here, we examined whether FGF23 antibody (FGF23-mAb) also improved the dentoalveolar features associated with XLH. Four-week-old male Hyp mice were injected weekly with 4 or 16 mg·kg -1 of FGF23-mAb for 2 months and compared to wild-type (WT) and vehicle (PBS) treated Hyp mice (n = 3-7 mice). Micro-CT analyses showed that both doses of FGF23-mAb restored dentin/cementum volume and corrected the enlarged pulp volume in Hyp mice, the higher concentration resulting in a rescue similar to WT levels. FGF23-mAb treatment also improved alveolar bone volume fraction and mineral density compared to vehicle-treated ones. Histology revealed improved mineralization of the dentoalveolar tissues, with a decreased amount of osteoid, predentin and cementoid. Better periodontal ligament attachment was also observed, evidenced by restoration of the acellular cementum. These preclinical data were consistent with the retrospective analysis of two patients with XLH showing that burosumab treatment improved oral features. Taken together, our data show that the dentoalveolar tissues are greatly improved by FGF23-mAb treatment, heralding its benefit in clinics for dental abnormalities., (© 2023. The Author(s).)

Introduction: Intermediate efficacy mu opioid receptor (MOR) agonists have potential to retain analgesic effectiveness while improving safety, but the optimal MOR efficacy for effective and safe opioid analgesia is unknown. Preclinical assays of pain-depressed behavior can assess effects of opioids and other candidate analgesics on pain-related behavioral depression, which is a common manifestation of clinically relevant pain and target of pain treatment. Accordingly, the present study goal was to validate a novel assay of pain-depressed locomotor behavior in mice and evaluate the role of MOR efficacy as a determinant of opioid analgesic effects and related safety measures., Methods: Male and female ICR mice were tested in a locomotor chamber consisting of 2 compartments connected by a doorway that contained a 1-inch-tall barrier. Dependent measures during 15-min behavioral sessions included crosses between compartments (which required vertical activity to surmount the barrier) and total movement counts (which required horizontal activity to break photobeams in each compartment)., Results and Discussion: Intraperitoneal injection of lactic acid (IP acid) produced a concentration- and time-dependent depression of both endpoints. Optimal blockade of IP acid-induced behavioral depression with minimal motor impairment was achieved with intermediate-efficacy MOR treatments that also produced less gastrointestinal-transit inhibition and respiratory depression than the high-efficacy MOR agonist fentanyl. Sex differences in treatment effects were rare. Overall, these findings validate a novel procedure for evaluating opioids and other candidate analgesic effects on pain-related behavioral depression in mice and support continued research with intermediate-efficacy MOR agonists as a strategy to retain opioid analgesic effectiveness with improved safety., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Negus, Akbarali, Kang, Lee, Marsh, Santos and Zhang.)

Identifying human leukocyte antigen (HLA) haplotype-homozygous donors for the generation of induced pluripotent stem (iPS) cell lines permits the construction of biobanks immunologically compatible with significant numbers of individuals for use in therapy. However, two questions must be addressed to create such a bank: how many cell lines are necessary to match most of the recipient population and how many people should be tested to find these donors? In Japan and the UK, 50 and 100 distinct HLA-A, -B, and -DRB1 triple-homozygous haplotypes would cover 90% of those populations, respectively. Using data from the Brazilian National Registry of Bone Marrow Donors (REDOME), encompassing 4,017,239 individuals, we identified 1,906 distinct triple-homozygous HLA haplotypes. In Brazil, 559 triple-homozygous cell lines cover 95% of the population, and 3.8 million people would have to be screened. Finally, we show the contribution of the 30 most frequent triple-homozygous HLA haplotypes in Brazil to populations of different countries., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Low-efficacy mu-opioid receptor (MOR) agonists represent promising therapeutics, but existing compounds (e.g., buprenorphine, nalbuphine) span a limited range of low MOR efficacies and have poor MOR selectivity. Accordingly, new and selective low-efficacy MOR agonists are of interest. A novel set of chiral C9-substituted phenylmorphans has been reported to display improved MOR selectivity and a range of high-to-low MOR efficacies under other conditions; however, a full opioid receptor binding profile for these drugs has not been described. Additionally, studies in mice will be useful for preclinical characterization of these novel compounds, but the pharmacology of these drugs in mice has also not been examined. Accordingly, the present study characterized the binding selectivity and in vitro efficacy of these compounds using assays of opioid receptor binding and ligand-stimulated [ 35 S]GTPɣS binding. Additionally, locomotor effects were evaluated as a first step for in vivo behavioral assessment in mice. The high-efficacy MOR agonist and clinically effective antidepressant tianeptine was included as a comparator. In binding studies, all phenylmorphans showed improved MOR selectivity relative to existing lower-efficacy MOR agonists. In the ligand-stimulated [ 35 S]GTPɣS binding assay, seven phenylmorphans had graded levels of sub-buprenorphine MOR efficacy. In locomotor studies, the compounds again showed graded efficacy with a rapid onset and ≥1 h duration of effects, evidence for MOR mediation, and minor sex differences. Tianeptine functioned as a high-efficacy MOR agonist. Overall, these in vitro and in vivo studies support the characterization of these compounds as MOR-selective ligands with graded MOR efficacy and utility for further behavioral studies in mice., (© 2023 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

This study evaluated climbing in mice as a tool to assess the expression and treatment of pain-related behavioral depression in male and female ICR mice. Mice were videotaped during 10-min sessions in a vertical plexiglass cylinder with wire mesh walls, and "Time Climbing" was scored by observers blind to treatments. Initial validation studies demonstrated that baseline climbing was stable across repeated days of testing and depressed by intraperitoneal injection of dilute lactic acid (IP acid) as an acute pain stimulus. Additionally, IP acid-induced depression of climbing was blocked by the positive-control non-steroidal anti-inflammatory drug (NSAID) ketoprofen but not by the negative control kappa opioid receptor agonist U69593. Subsequent studies examined effects of single-molecule opioids (fentanyl, buprenorphine, naltrexone) and of fixed-proportion fentanyl/naltrexone mixtures (10:1, 3.2:1, and 1:1) that vary in their efficacy at the mu opioid receptor (MOR). Opioids administered alone produced a dose- and efficacy-dependent decrease in climbing, and fentanyl/naltrexone-mixture data indicated that climbing in mice is especially sensitive to disruption by even low-efficacy MOR activation. Opioids administered as a pretreatment to IP acid failed to block IP acid-induced depression of climbing. Taken together, these findings support the utility of climbing in mice as an endpoint to evaluate candidate-analgesic effectiveness both to (a) produce undesirable behavioral disruption when the test drug is administered alone, and (b) produce a therapeutic blockade of pain-related behavioral depression. The failure of MOR agonists to block IP acid-induced depression of climbing likely reflects the high sensitivity of climbing to disruption by MOR agonists., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Santos, Giddings, Kandil and Negus.)

Background: Aggression is one manifestation of behavioral disturbances in neurodegenerative disease with emerging literature suggesting a high prevalence in Parkinson's disease and related disorders (PDRD)., Objectives: Our aim was to describe characteristics, associated factors, and consequences of aggression towards caregivers in PDRD., Methods: This is a convergent mixed methods study, leveraging data from 296 PDRD patient-caregiver dyads in a clinical trial of palliative care and semi-structured interviews with a subgroup of 14 caregivers who reported aggression. The primary outcome was baseline caregiver-reported aggression. Using multivariate linear regression, baseline dyad characteristics (eg, measures of disease, psychosocial issues, caregiver strain) were examined to identify factors associated with aggression. Thematic analysis of interviews was used to augment these findings., Results: Associated variables included disease duration ( r  = 0.15, P  < 0.05), patient grief ( r  = 0.22, P < 0.001), symptom burden ( r  = 0.18, r  < 0.01), resistance to care ( r  = 0.40, P  < 0.01), caregivers' depression ( r  = 0.16, P  < 0.05), and caregiving burden ( r  = 0.34, P  < 0.001). We identified five themes: (1) Aggressive behaviors range from verbal abuse to threats of physical violence; (2) Caregivers believe that aggressive behaviors result from the difficulty patients experience in coping with disease progression and related losses; (3) Caregivers' stress and mental health are worsened by aggressive behaviors; (4) Aggressive behaviors negatively affect patient-caregiver relationships; (5) Caregivers are ill-prepared to manage aggressive behaviors and cope with the consequences on their own., Conclusions: Aggression in PDRD is driven by diverse factors (eg, grief, fluctuations in cognition) with serious consequences for caregivers. Neurologists and movement specialists should consider screening for aggression while prioritizing caregiver education and wellbeing., Competing Interests: Study funding provided by the National Institute on Aging's (NIA) Multidisciplinary Research Training in Palliative Care and Aging award number T32AG044296. The authors declare there are no conflicts of interest relevant to this work., (© 2022 International Parkinson and Movement Disorder Society.)

Rationale: Tianeptine is a mu-opioid receptor (MOR) agonist with increasing reports of abuse in human populations. Preclinical data regarding the abuse potential and other opioid-like adverse effects of tianeptine at supratherapeutic doses are sparse., Objectives: The present study evaluated tianeptine in a rat model of abuse potential assessment and in mouse models of motor, gastrointestinal, and respiratory adverse effects., Methods: Abuse potential was assessed in adult male Sprague-Dawley rats using an intracranial self-stimulation (ICSS) procedure to determine effects of acute and repeated tianeptine on responding for electrical brain stimulation. Male ICR mice were used to determine the effects of tianeptine in assays of locomotor behavior and gastrointestinal motility. Male Swiss-Webster mice were monitored for respiratory changes using whole-body plethysmography., Results: In rats, acute tianeptine produced weak and delayed evidence for abuse-related ICSS facilitation at an intermediate dose (10 mg/kg, IP) and pronounced, naltrexone-preventable ICSS depression at a higher dose (32 mg/kg, IP). Repeated 7-day tianeptine (10 and 32 mg/kg/day, IP) produced no increase in abuse-related ICSS facilitation, only modest tolerance to ICSS depression, and no evidence of physical dependence. In mice, tianeptine produced dose-dependent, naltrexone-preventable locomotor activation. Tianeptine (100 mg/kg, SC) also significantly inhibited gastrointestinal motility and produced naloxone-reversible respiratory depression., Conclusions: Tianeptine presents as a MOR agonist with resistance to tolerance and dependence in our ICSS assay in rats, and it has lower abuse potential by this metric than many commonly abused opioids. Nonetheless, tianeptine produces MOR agonist-like acute adverse effects that include motor impairment, constipation, and respiratory depression., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Mu opioid receptor (MOR) agonists produce locomotor hyperactivity in mice as one sign of opioid-induced motor disruption. The goal of this study was to evaluate the degree of MOR efficacy required to produce this hyperactivity. Full dose-effect curves were determined for locomotor activation produced in male and female Institute of Cancer Research (ICR) mice by (1) eight different single-molecule opioids with high to low MOR efficacy and (2) a series of fixed-proportion fentanyl/naltrexone mixtures with high to low fentanyl proportions. Data from the mixtures were used to quantify the efficacy requirement for MOR agonist-induced hyperactivity relative to efficacy requirements determined previously for other MOR agonist effects. Specifically, efficacy requirement was quantified as the EP50 value, which is the "Effective Proportion" of fentanyl in a fentanyl/naltrexone mixture that produces a maximal effect equal to 50% of the maximal effect of fentanyl alone. Maximal hyperactivity produced by each drug and mixture in the present study correlated with previously published data for maximal stimulation of GTPɣS binding in MOR-expressing Chinese hamster ovary cells as an in vitro measure of relative efficacy. Additionally, the EP 50 value for hyperactivity induced by fentanyl/naltrexone mixtures indicated that opioid-induced hyperactivity in mice has a relatively high efficacy requirement in comparison with some other MOR agonist effects, and in particular is higher than the efficacy requirement for thermal antinociception in mice or fentanyl discrimination in rats. Taken together, these data show that MOR agonist-induced hyperactivity in mice is efficacy dependent and requires relatively high levels of MOR agonist efficacy for its full expression. SIGNIFICANCE STATEMENT: Mu opioid receptor (MOR) agonist-induced hyperlocomotion in mice is dependent on the MOR efficacy of the agonist and requires a relatively high degree of efficacy for its full expression., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

The functional interactions between opioid and chemokine receptors have been implicated in the pathological process of chronic pain. Mounting studies have indicated the possibility that a MOR-CXCR4 heterodimer may be involved in nociception and related pharmacologic effects. Herein we have synthesized a series of bivalent ligands containing both MOR agonist and CXCR4 antagonist pharmacophores with an aim to investigate the functional interactions between these two receptors. In vitro studies demonstrated reasonable recognition of designed ligands at both respective receptors. Further antinociceptive testing in mice revealed compound 1a to be the most promising member of this series. Additional molecular modeling studies corroborated the findings observed. Taken together, we identified the first bivalent ligand 1a showing promising antinociceptive effect by targeting putative MOR-CXCR4 heterodimers, which may serve as a novel chemical probe to further develop more potent bivalent ligands with potential application in analgesic therapies for chronic pain management., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Mutations in the PHEX gene lead to X-linked hypophosphatemia (XLH), a form of inherited rickets featuring elevated fibroblast growth factor 23 (FGF23), reduced 1,25-dihydroxyvitamin D (1,25D), and hypophosphatemia. Hyp mutant mice replicate the XLH phenotype, including dentin, alveolar bone, and cementum defects. We aimed to compare effects of 1,25D versus FGF23-neutralizing antibody (FGF23Ab) monotherapies on Hyp mouse dentoalveolar mineralization. Male Hyp mice, either injected subcutaneously with daily 1,25D or thrice weekly with FGF23 blocking antibody from 2 to 35 d postnatal, were compared to wild-type (WT) controls and untreated Hyp mice. Mandibles were analyzed by high-resolution micro-computed tomography (micro-CT), histology, and immunohistochemistry. Both interventions maintained normocalcemia, increased serum phosphate levels, and improved dentoalveolar mineralization in treated versus untreated Hyp mice. 1,25D increased crown dentin volume and thickness and root dentin/cementum volume, whereas FGF23Ab effects were limited to crown dentin volume. 1,25D increased bone volume fraction, bone mineral density, and tissue mineral density in Hyp mice, whereas FGF23Ab failed to significantly affect these alveolar bone parameters. Neither treatment fully attenuated dentin and bone defects to WT levels, and pulp volumes remained elevated regardless of treatment. Both treatments reduced predentin thickness and improved periodontal ligament organization, while 1,25D promoted a more profound improvement in acellular cementum thickness. Altered cell densities and lacunocanalicular properties of alveolar and mandibular bone osteocytes and cementocytes in Hyp mice were partially corrected by either treatment. Neither treatment normalized the altered distributions of bone sialoprotein and osteopontin in Hyp mouse alveolar bone. Moderate improvements from both 1,25D and FGF23Ab treatment regimens support further studies and collection of oral health data from subjects receiving a newly approved anti-FGF23 therapy. The inability of either treatment to fully correct Hyp mouse dentin and bone prompts further experiments into underlying pathological mechanisms to identify new therapeutic approaches.

Cementum is a mineralized tissue that covers tooth roots and functions in the periodontal attachment complex. Cementocytes, resident cells of cellular cementum, share many characteristics with osteocytes, are mechanoresponsive cells that direct bone remodeling based on changes in loading. We hypothesized that cementocytes play a key role during orthodontic tooth movement (OTM). To test this hypothesis, we used 8-week-old male Wistar rats in a model of OTM for 2, 7, or 14 days (0.5 N), whereas unloaded contralateral teeth served as controls. Tissue and cell responses were analyzed by high-resolution micro-computed tomography, histology, tartrate-resistant acid phosphatase staining for odontoclasts/osteoclasts, and transmission electron microscopy. In addition, laser capture microdissection was used to collect cellular cementum, and extracted proteins were identified by liquid chromatography coupled to tandem mass spectrometry. The OTM model successfully moved first molars mesially more than 250 μm by 14 days introducing apoptosis in a small number of cementocytes and areas of root resorption on mesial and distal aspects. Cementocytes showed increased nuclear size and proportion of euchromatin suggesting cellular activity. Proteomic analysis identified 168 proteins in cellular cementum with 21 proteins found only in OTM sites and 54 proteins only present in control samples. OTM-down-regulated several extracellular matrix proteins, including decorin, biglycan, asporin, and periostin, localized to cementum and PDL by immunostaining. Furthermore, type IV collagen (COL14A1) was the protein most down-regulated (-45-fold) by OTM and immunolocalized to cells at the cementum-dentin junction. Eleven keratins were significantly increased by OTM, and a pan-keratin antibody indicated keratin localization primarily in epithelial remnants of Hertwig's epithelial root sheath. These experiments provide new insights into biological responses of cementocytes and cellular cementum to OTM., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Cellular cementum, a mineralized tissue covering apical tooth roots, grows by apposition to maintain the tooth in its occlusal position. We hypothesized that resident cementocytes would show morphological changes in response to cementum apposition, possibly implicating a role in cementum biology., Methods: Mandibular first molars were induced to super-erupt (EIA) by extraction of maxillary molars, promoting rapid new cementum formation. Tissue and cell responses were analyzed at 6 and/or 21 days post-procedure (dpp)., Results: High-resolution micro-computed tomography (micro-CT) and confocal laser scanning microscopy showed increased cellular cementum by 21 dpp. Transmission electron microscopy (TEM) revealed that cementocytes under EIA were 50% larger than control cells, supported by larger pore sizes detected by micro-CT. Cementocytes under EIA displayed ultrastructural changes consistent with increased activity, including increased cytoplasm and nuclear size. We applied EIA to Hyp mutant mice, where cementocytes have perilacunar hypomineralization defects, to test cell and tissue responses in an altered mechanoresponsive milieu. Hyp and WT molars displayed similar super-eruption, with Hyp molars exhibiting 28% increased cellular cementum area versus 22% in WT mice at 21 dpp. Compared to control, Hyp cementocytes featured well-defined, disperse euchromatin and a thick layer of peripherally condensed heterochromatin in nuclei, indicating cellular activity. Immunohistochemistry (IHC) for cementum markers revealed intense dentin matrix protein-1 expression and abnormal osteopontin deposition in Hyp mice. Both WT and Hyp cementocytes expressed gap junction protein, connexin 43., Conclusion: This study provides new insights into the EIA model and cementocyte activity in association with new cementum formation., (© 2021 American Academy of Periodontology.)

Older age and medical comorbidity are factors associated with more severe illness and risk of death due to COVID-19 infection. Social distancing is an important public health strategy for controlling the spread of the virus and minimizing its impact on the older adult population. It comes at a cost, however. Loneliness is associated with myriad adverse health outcomes, one of which is impaired immune functioning, which adds even greater risk for coronavirus infection, complications and death. Older adults, therefore, are at compound risk, making effective management of loneliness and social isolation in our older patients a high priority target for preventive intervention. In this paper, the authors describe a cognitive-behavioral framework for social connectedness, including evidence-informed strategies clinicians can use to help patients develop a "Connections Plan" to stay connected and promote their social, mental, and physical health during "social distancing" restrictions. This set of strategies can be provided during brief (30 minute) telephone sessions and is analogous to creating a "Safety Plan" for suicide risk. The approach is illustrated with three case examples., (Copyright © 2020 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

The extensive allelic variability observed in several genes related to the immune response and its significance in different areas including transplantation, disease association studies, diversity in human populations, among many others, has led the scientific community to analyse these variants among individuals. Serving as an electronic data warehouse, the Allele Frequency Net Database (AFND, http://www.allelefrequencies.net) contains data on the frequency of immune related genes and their corresponding alleles from more than 1700 worldwide population samples covering more than ten million unrelated individuals. The collection of population data sets available in AFND encompasses different polymorphic regions including the highly-polymorphic human leukocyte antigen (HLA) system for which more than 1200 populations are available. In this article, we provide an insight of the high diversity found in the HLA region by examining population data sets stored in AFND, as well as a description of the available data sets for further analyses., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to answer the PICO question: in adults with periodontitis, does subgingival delivery of natural products (NP) after scaling and root planing (SRP) results in a better reduction of probing pocket depth (PPD) when compared with SRP alone or SRP plus placebo?, Material and Methods: A search for trials was carried out in eight databases. Two independent investigators performed all steps of this review. PPD reduction, clinical attachment level (CAL) gain, gingival inflammation, and biofilm accumulation reduction were investigated. We conducted meta-analyses where data could be pooled., Results: Searches yielded 4771 records, in which 27 trials fulfilled the eligibility. There was a large heterogeneity among trials (I 2  > 0.69, χ 2  < 0.000). Only four studies were at low risk of bias. The evidence quality was very low. The effectiveness of NP was demonstrated in a follow-up of 3-6 months considering PPD reduction (8 trials: 0.72 mm [95%CI: 0.23, 1.22]) and CAL gain (5 trials: 1.07 mm [95%CI: 0.36, 1.78]). A significant reduction in periodontal inflammation favors the use of NP. The biofilm accumulation reduction effect of NP was very weak or non-significant., Conclusion: Although the high risk of bias and large heterogeneity of trials impose some restrictions on the validity of effect estimate, this review indicates that adjunctive NP better reduced the PPD when compared to SRP alone or SRP plus placebo in a follow-up of 3-6 months., Clinical Relevance: The evidence of non-responsive patients to conventional periodontal therapy highlights the need for therapeutic alternatives to treat periodontitis., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

This study evaluated a battery of pain-stimulated, pain-depressed, and pain-independent behaviors for preclinical pharmacological assessment of candidate analgesics in mice. Intraperitoneal injection of dilute lactic acid (IP acid) served as an acute visceral noxious stimulus to produce four pain-related behaviors in male and female ICR mice: stimulation of 1) stretching, 2) facial grimace, 3) depression of rearing, and 4) depression of nesting. Additionally, nesting and locomotion in the absence of the noxious stimulus were used to assess pain-independent drug effects. These six behaviors were used to compare effects of two mechanistically distinct but clinically effective positive controls (ketoprofen and oxycodone) and two negative controls that are not clinically approved as analgesics but produce either general motor depression (diazepam) or motor stimulation (amphetamine). We predicted that analgesics would alleviate all IP acid effects at doses that did not alter pain-independent behaviors, whereas negative controls would not. Consistent with this prediction, ketoprofen (0.1-32 mg/kg) produced the expected analgesic profile, whereas oxycodone (0.32-3.2 mg/kg) alleviated all IP acid effects except depression of rearing at doses lower than those that altered pain-independent behaviors. For the negative controls, diazepam (1-10 mg/kg) failed to block IP acid-induced depression of either rearing or nesting and only decreased IP acid-stimulated behaviors at doses that also decreased pain-independent behaviors. Amphetamine (0.32-3.2 mg/kg) alleviated all IP acid effects but only at doses that also stimulated locomotion. These results support utility of this model as a framework to evaluate candidate-analgesic effects in a battery of complementary pain-stimulated, pain-depressed, and pain-independent behavioral endpoints. SIGNIFICANCE STATEMENT: Preclinical assays of pain and analgesia often yield false-positive effects with candidate analgesics. This study used two positive-control analgesics (ketoprofen, oxycodone) and two active negative controls (diazepam, amphetamine) to validate a strategy for distinguishing analgesics from nonanalgesics by profiling drug effects in a battery of complementary pain-stimulated, pain-depressed, and pain-independent behaviors in male and female mice., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Pharmacodynamic efficacy of drugs to activate their receptors is a key determinant of drug effects, and intermediate-efficacy agonists are often useful clinically because they retain sufficient efficacy to produce therapeutically desirable effects while minimizing undesirable effects. Molecular mechanisms of efficacy are not well understood, so rational drug design to control efficacy is not yet possible; however, receptor theory predicts that fixed-proportion mixtures of an agonist and antagonist for a given receptor can be adjusted to precisely control net efficacy of the mixture in activating that receptor. Moreover, the agonist proportion required to produce different effects provides a quantitative scale for comparing efficacy requirements across those effects. To test this hypothesis, the present study evaluated effectiveness of fixed-proportion agonist/antagonist mixtures to produce in vitro and in vivo effects mediated by μ -opioid receptors (MOR) and cannabinoid type 1 receptors (CB 1 R). Mixtures of 1) the MOR agonist fentanyl and antagonist naltrexone and 2) the CB 1 R agonist CP55,940 and antagonist/inverse agonist rimonabant were evaluated in an in vitro assay of ligand-stimulated guanosine 5'- O -(3-[ 35 S]thio)triphosphate binding and an in vivo assay of thermal nociception in mice. For both agonist/antagonist pairs in both assays, increasing agonist proportions produced graded increases in maximal mixture effects, and lower agonist proportions were sufficient to produce in vivo than in vitro effects. These findings support the utility of agonist-antagonist mixtures as a strategy to control net efficacy of receptor activation and to quantify and compare efficacy requirements across a range of in vitro and in vivo endpoints. SIGNIFICANCE STATEMENT: Manipulation of agonist proportion in agonist/antagonist mixtures governs net mixture efficacy at the target receptor. Parameters of agonist/antagonist mixture effects can provide a quantitative metric for comparison of efficacy requirements across a wide range of conditions., Competing Interests: No author has an actual or perceived conflict of interest with the contents of this article., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Erosive tooth wear has been a highly prevalent and emerging phenomenon related to eating habits of the population. Aim: This study sought to investigate industrialized fruit juices exposure in enamel and dentine substrates in terms of erosive effect., Material and Methods: Human enamel and dentine specimens were randomized into 8 groups (n=8): Grape juice - Ades®, Grape juice - Del Valle Kapo®, Grape juice - Aurora®, Orange juice - Del Valle Kapo®, Orange juice - Ades®, Strawberry juice - Mais Vita®, Strawberry juice - Ades®, Citrus fruit juice - Tampico®. Specimens were submitted to an in vitro erosive challenge and to a microhardness test to evaluate the percentage of surface microhardness loss. The pH, titratable acidity, buffering capacity, degree of saturation and critical pH concerning hydroxyapatite and fluorapatite of the juices were measured as well as their composition of calcium, phosphate, fluoride, and total protein. Data were submitted to the analysis of variance and multivariate linear regression (α=0.05)., Results: All test agents were undersaturated concerning hydroxyapatite and fluorapatite. A significant interaction between the type of juice and substrate was found (α=0.000, β=0.99). However, Orange juice - Del Valle Kapo®, Orange juice - Ades®, and Strawberry juice - Mais Vitta® demonstrated no difference between substrates. Grape juice - Ades® promoted less mineral than other juices in enamel and dentine. The calcium concentration in juices was a protective variable for microhardness loss in both substrates., Conclusions: The erosive effect of industrialized fruit juices affects enamel differently from dentine, and this effect differed between some, but not all, tested juices. Key words: Tooth erosion, dental enamel, dentine. beverages, food habits., Competing Interests: Conflicts of interest The authors declare no conflicts of interest in terms of the authorship and/or publication of this article., (Copyright: © 2021 Medicina Oral S.L.)

The discoidin domain receptors, DDR1 and DDR2, are nonintegrin collagen receptors and tyrosine kinases. DDRs regulate cell functions, and their extracellular domains affect collagen fibrillogenesis and mineralization. Based on the collagenous nature of dentoalveolar tissues, we hypothesized that DDR1 plays an important role in dentoalveolar development and function. Radiography, micro-computed tomography (micro-CT), histology, histomorphometry, in situ hybridization (ISH), immunohistochemistry (IHC), and transmission electron microscopy (TEM) were used to analyze Ddr1 knockout ( Ddr1 -/- ) mice and wild-type (WT) controls at 1, 2, and 9 mo, and ISH and quantitative polymerase chain reaction (qPCR) were employed to assess Ddr1 / DDR1 messenger RNA expression in mouse and human tissues. Radiographic images showed normal molars but abnormal mandibular condyles, as well as alveolar bone loss in Ddr1 -/- mice versus WT controls at 9 mo. Histological, histomorphometric, micro-CT, and TEM analyses indicated no differences in enamel or dentin Ddr1 -/- versus WT molars. Total volumes (TVs) and bone volumes (BVs) of subchondral and ramus bone of Ddr1 -/- versus WT condyles were increased and bone volume fraction (BV/TV) was reduced at 1 and 9 mo. There were no differences in alveolar bone volume at 1 mo, but at 9 mo, severe periodontal defects and significant alveolar bone loss (14%; P  < 0.0001) were evident in Ddr1 -/- versus WT mandibles. Histology, ISH, and IHC revealed disrupted junctional epithelium, connective tissue destruction, bacterial invasion, increased neutrophil infiltration, upregulation of cytokines including macrophage colony-stimulating factor, and 3-fold increased osteoclast numbers ( P  < 0.05) in Ddr1 -/- versus WT periodontia at 9 mo. In normal mouse tissues, ISH and qPCR revealed Ddr1 expression in basal cell layers of the oral epithelia and in immune cells. We confirmed a similar expression pattern in human oral epithelium by ISH and qPCR. We propose that DDR1 plays an important role in periodontal homeostasis and that absence of DDR1 predisposes mice to periodontal breakdown.

Objective: To evaluate patient perception of the smile focused on analysis of the upper incisors., Design: Cross-sectional study., Setting: Department of Clinical and Social Dentistry at Federal University of Paraíba, João Pessoa, Brazil., Participants: The sample consisted of 135 individuals (73 women and 62 men)., Methods: Images with different characteristics associated with the incisal edges were shown at random and analysed using a Likert scale. Data were analysed using the Chi-square test or Fisher's exact test with a statistically significant difference ( P < 0.05)., Results: Smile I (difference of 1.5 mm in relation to the central incisor and lateral) was considered the most aesthetic, while Smile III (no difference in height between the central and lateral incisors) was the least aesthetic. A significant difference was found between perception of smile II (difference of 1 mm in relation to the central incisor and lateral) and age groups ( P < 0.005), with 31% (n = 13) of individuals aged 45-64 years considering smile II as not pleasant, 4.4% (n = 2) aged 15-24 years and 8.3% (n=4) aged 25-44 years and 4.4% (n = 2) aged 15-24 years considering the same. A significant difference was also found in relation to educational background of the assessor and smile perception, with smile III ( P = 0.0441) and smile IV ( P = 0.0053) considered the most aesthetic ( P = 0.0116)., Conclusion: The smile considered most attractive among the sample was that with 1.5 mm steepness between the central and lateral incisors, while a flat smile arc was considered least attractive.

Minors' mental health is a subject of high global concern. Understanding the factors that influence their mental health is essential to improving the health of future generations. In this study, an analysis of the Strengths and Difficulties Questionnaire's usefulness is carried out, as a validated tool, recognized in Spain and internationally, for the measurement of minors' mental health. In turn, the influence of the variables of gender, age, and physical health, along with the occupational social class of parents on Spanish minors' mental health, has been analyzed. Spanish minors with good physical health and of parents with middle and higher education, as well as in an occupational social class, are less likely to suffer mental health problems. On the other hand, it seems that internalizing symptoms are more likely in girls, and externalizing symptoms are more likely in boys. However, when a global measure of mental health is made without specific subscales, the effects of gender and age diverge greatly, according to the studies. Although there are examples of current research using the same measurement tool, there is still a need for many more international studies that are coordinated using the same methodology. This study identifies the factors which the international and Spanish scientific literature has revealed as being determinants in minors' mental health. Finally, it is essential that the influence of these factors be assessed in the areas of primary care and mental health to facilitate better detection, intervention, or prevention of mental health problems in today's children, as well as the children of future generations.

Background: This study aimed to evaluate the influence of surface treatments on the bond strength between a zirconia-based ceramic and two resin cements., Methods: Eighty blocks (5.25×3.74×4.5 mm) of a zirconia-based ceramic were divided into eight groups (N.=10) according to the factors "surface treatment" (air-particle abrasion with Al2O3 or Al2O3/SiO2 and zirconia primer) and "cement" (conventional resin cement and self-adhesive resin cement). After the surface treatments, cylinders of each resin cement (Ø=3.5 mm, height: 3 mm) were built up on the zirconia surface and photo-activated (40 s). The samples were stored in water for 30 days at 37 °C, followed by shear bond strength test in a universal testing machine (1 mm/min). Data were analyzed by ANOVA and Tukey test (α=0.05)., Results: Regarding the surface treatments, all strategies were statistically different from each other. The Cojet achieved the higher bond strength values, followed by Signum Zirconia Bond. The resin cements were also statistically different from each other, since the U200 achieved higher bond strength values. The interaction between the factors was also significant. Most of the failures were adhesive and mixed., Conclusions: Regardless of the cement used, the air-particle abrasion with alumina coated by silica particles improved bond strength.

The allele frequency net database (AFND, http://www.allelefrequencies.net ) is an online web-based repository that contains information on the frequencies of immune-related genes and their corresponding alleles in worldwide human populations. At present, the system contains data from 1505 populations in more than ten million individuals on the frequency of genes from different polymorphic regions including data for the human leukocyte antigens (HLA) system. This resource has been widely used in a variety of contexts such as histocompatibility, immunology, epidemiology, pharmacogenetics, and population genetics, among many others. In this chapter, we present some of the more commonly used searching mechanisms and some of the most recent developments included in AFND.

Research on minors' mental health is an increasingly developing area. Given the increased prevalence of disorders, it seems necessary to analyze the factors that can affect poor mental health. This study analyzes the influence of occupational class, educational level, age, sex and perceived mental health of Spanish children, which is measured through the Strengths and Difficulties Questionnaire. The sample consists of 3599 minors between 4 and 14 years old, who were interviewed through the Spanish National Health Survey 2011. Our results indicating the significant ( p < 0.05) relationship between mental health, occupational class (OR 0.533) and minors' health in the last year (OR 0.313) are shown. However, gender (OR 1.187) and educational level of Pre-School Education in relation to Secondary Education (OR 1.174) and Primary Education (OR 0.996) do not generate significant differences. In conclusion, we consider it necessary to design and implement public policies aimed at improving the care system for children who have had poor or regular health in the last year, and whose parents are positioned in the lowest part of the occupational scale., Competing Interests: The authors declare no conflict of interest.

Raman spectroscopy has become an essential technique to characterize and investigate graphene and many other two-dimensional materials. However, there is still a lack of consensus on the Raman signature and phonon dispersion of atomically thin boron nitride (BN), which has many unique properties distinct from graphene. Such a knowledge gap greatly affects the understanding of the basic physical and chemical properties of atomically thin BN as well as the use of Raman spectroscopy to study these nanomaterials. Here, we use both experiment and simulation to reveal the intrinsic Raman signature of monolayer and few-layer BN. We find experimentally that atomically thin BN without interaction with a substrate has a G band frequency similar to that of bulk hexagonal BN (hBN), but strain induced by the substrate can cause a pronounced Raman shift. This is in excellent agreement with our first-principles density functional theory (DFT) calculations at two levels of theory, including van der Waals dispersion forces (opt-vdW) and a fraction of the exact exchange from Hartree-Fock (HF) theory through the hybrid HSE06 functional. Both calculations demonstrate that the intrinsic E 2g mode of BN does not depend sensibly on the number of layers. Our simulations also suggest the importance of the exact exchange mixing parameter in calculating the vibrational modes in BN, as it determines the fraction of HF exchange included in the DFT calculations.

Whilst immune-mediated adverse drug reactions (ADRs) are rare, they are potentially life-threatening and present a major problem for clinicians. The underlying mechanisms that cause ADRs are not fully understood although genomewide association studies (GWAS) and case-control investigations have associated human leucocyte antigen (HLA) alleles as risk factors. There is evidence that a patient's ethnic background can have an impact on their risk of developing an ADR. This review summarizes the evidence related to HLA alleles and ADRs with particular focus on patient ethnicity. Our analysis indicated that many of the alleles which have been associated with ADRs are found at higher frequencies in Asian populations. The data also showed that many of the alleles that are reported to be statistically significantly associated with ADRs are in linkage disequilibrium with each other and that they form haplotypes specific to certain ethnicities indicating at least some of the allele associations may not be causal., (© 2017 John Wiley & Sons Ltd.)

Background: Presepsin is a promising biomarker for the diagnosis and prognosis of sepsis. However, results reported about its value to diagnose sepsis in an emergency department (ED) are controversial, probably due to differences in the design of the studies. We have evaluated the diagnostic accuracy of presepsin for infection and sepsis, compared with procalcitonin (PCT) and C-reactive protein (CRP), in patients presenting to the emergency department (ED) with suspected infection., Methods: 223 patients with suspected infection were enrolled for the study. Blood samples were collected on admission for measurement of biomarkers. Definitive diagnosis was obtained afterwards by analysis of digital medical records. Receiver operating characteristic (ROC) curve analysis was conducted to determine the diagnostic accuracy., Results: Infection was confirmed in 200 patients, including 130 with non-complicated infection and 70 with sepsis. Median CRP, PCT and presepsin levels were significantly higher in patients with infection and sepsis. PCT was the biomarker with the highest performance for infection (ROC AUC: 0.910); for sepsis, PCT (ROC AUC: 0.815) and presepsin (ROC AUC: 0.775) shown a similar performance., Conclusion: Although presepsin is a valuable biomarker for diagnosis of infection and sepsis, its diagnostic accuracy in our study does not improve that of PCT. Its introduction in clinical practice is not justified., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Performance comparison of selected photodiodes for usage as radiation detectors for radio-protection is presented. In this study, based on the criteria of minimum sensitive area of 5mm 2 , minimum half angle 60° and low cost, four commercial photodiodes are selected for evaluation: SFH205, SFH206, BPW34, and BPX90F. Photodiodes are low cost, small volume and lightweight detectors. As an electronic transducer, photodiode detector is an attractive approach for the development of low power portable electronic dosimeter for direct-reading real-time radiation dose measurement. The devices have been studied with respect to sensitivity (efficiency) in X-rays and gamma rays detection, repeatability and linearity in air kerma., (Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Understanding the microscopic mechanisms of electronic excitation in organic photovoltaic cells is a challenging problem in the design of efficient devices capable of performing sunlight harvesting. Here we develop and apply an ab initio approach based on time-dependent density functional theory and Ehrenfest dynamics to investigate photoinduced charge transfer in small organic molecules. Our calculations include mixed quantum-classical dynamics with ions moving classically and electrons quantum mechanically, where no experimental external parameter other than the material geometry is required. We show that the behavior of photocarriers in zinc phthalocyanine (ZnPc) and C60 systems, an effective prototype system for organic solar cells, is sensitive to the atomic orientation of the donor and the acceptor units as well as the functionalization of covalent molecules at the interface. In particular, configurations with the ZnPc molecules facing on C60 facilitate charge transfer between substrate and molecules that occurs within 200 fs. In contrast, configurations where ZnPc is tilted above C60 present extremely low carrier injection efficiency even at longer times as an effect of the larger interfacial potential level offset and higher energetic barrier between the donor and acceptor molecules. An enhancement of charge injection into C60 at shorter times is observed as binding groups connect ZnPc and C60 in a dyad system. Our results demonstrate a promising way of designing and controlling photoinduced charge transfer on the atomic level in organic devices that would lead to efficient carrier separation and maximize device performance.

Gate-tunable two-dimensional (2D) materials-based quantum capacitors (QCs) and van der Waals heterostructures involve tuning transport or optoelectronic characteristics by the field effect. Recent studies have attributed the observed gate-tunable characteristics to the change of the Fermi level in the first 2D layer adjacent to the dielectrics, whereas the penetration of the field effect through the one-molecule-thick material is often ignored or oversimplified. Here, we present a multiscale theoretical approach that combines first-principles electronic structure calculations and the Poisson-Boltzmann equation methods to model penetration of the field effect through graphene in a metal-oxide-graphene-semiconductor (MOGS) QC, including quantifying the degree of "transparency" for graphene two-dimensional electron gas (2DEG) to an electric displacement field. We find that the space charge density in the semiconductor layer can be modulated by gating in a nonlinear manner, forming an accumulation or inversion layer at the semiconductor/graphene interface. The degree of transparency is determined by the combined effect of graphene quantum capacitance and the semiconductor capacitance, which allows us to predict the ranking for a variety of monolayer 2D materials according to their transparency to an electric displacement field as follows: graphene > silicene > germanene > WS2 > WTe2 > WSe2 > MoS2 > phosphorene > MoSe2 > MoTe2, when the majority carrier is electron. Our findings reveal a general picture of operation modes and design rules for the 2D-materials-based QCs.

Human leukocyte antigens (HLA) are an important family of genes involved in the immune system. Their primary function is to allow the host immune system to be able to distinguish between self and non-self peptides-e.g. derived from invading pathogens. However, these genes have also been implicated in immune-mediated adverse drug reactions (ADRs), presenting a problem to patients, clinicians and pharmaceutical companies. We have previously developed the Allele Frequency Net Database (AFND) that captures the allelic and haplotype frequencies for these HLA genes across many healthy populations from around the world. Here, we report the development and release of the HLA-ADR database that captures data from publications where HLA alleles and haplotypes have been associated with ADRs (e.g. Stevens-Johnson Syndrome/toxic epidermal necrolysis and drug-induced liver injury). HLA-ADR was created by using data obtained through systematic review of the literature and semi-automated literature mining. The database also draws on data already present in AFND allowing users to compare and analyze allele frequencies in both ADR patients and healthy populations. The HLA-ADR database provides clinicians and researchers with a centralized resource from which to investigate immune-mediated ADRs.Database URL: http://www.allelefrequencies.net/hla-adr/., (© The Author(s) 2016. Published by Oxford University Press.)

While liquid exfoliation is a powerful technique to produce defect-free nanosheets in large quantities, its usefulness is limited by broad nanosheet thickness distributions and low monolayer contents. Here we demonstrate liquid processing techniques, based on iterative centrifugation cascades, which can be designed to achieve either highly efficient nanosheet size-selection and/or monolayer enrichment. The resultant size-selected dispersions were used to establish quantitative metrics to determine monolayer volume fraction, as well as mean nanosheet size and thickness, from standard spectroscopic measurements. Such metrics allowed us to design and optimize centrifugation cascades to enrich liquid exfoliated WS2 dispersions up to monolayer contents of 75%. Monolayer-rich dispersions show relatively bright photoluminescence with narrow line widths (<35 meV) indicating the high quality of the nanosheets. The enriched dispersions display extinction spectra with distinct features, which also allow the direct estimation of monolayer contents.

This study aimed to identify and compare the diversity between two areas within different matrices located in the Mesophytic Semideciduous Forest; to compare composition and diversity registered to other assemblages; and to evaluate which criteria used here were the most important when sampling them. Data was obtained from September 2011 to March 2012 from 10 sites with different habitats in two areas of mid northern state of Paraná, southern Brazil. We recorded 18 species. Alfa-diversity between the areas did not vary, but the population within one of them was more stable, suggesting better distribution and equity of species in the available habitat. Beta-diversity in the region was high; a result attributed to the species Dendropsophus nanus. Comparing the sampled areas to others in the Semideciduous Forest, the quantity of sampled breeding sites was the most important variable for higher records of richness. Geographical distance was a determinant factor for the distinction between localities. Different factors were determinant for the variation in richness and composition of species in the area. Hence, the conservation of fragments and their associated habitat need to be prioritized.

Objective: Determining which is the most effective solution (heparin flush compared to 0.9% saline flush) for reducing the risk of occlusions in central venous catheters (CVC) in adults., Method: The systematic review followed the principles proposed by the Cochrane Handbook; critical analysis, extraction and synthesis of data were performed by two independent researchers; statistical analysis was performed using the RevMan program 5.2.8., Results: Eight randomized controlled trials and one cohort study were included and the results of the meta-analysis showed no difference (RR=0.68, 95% CI=0.41-1.10; p=0.12). Analysis by subgroups showed that there was no difference in fully deployed CVC (RR=1.09, CI 95%=0.53-2.22; p=0.82); Multi-Lumen CVC showed beneficial effects in the heparin group (RR=0.53, CI 95%=0.29-0.95; p=0.03); in Double-Lumen CVC for hemodialysis (RR=1.18, CI 95%=0.08-17.82; p=0.90) and Peripherally inserted CVC (RR=0.14, CI 95%=0.01-2.60; p=0.19) also showed no difference., Conclusion: Saline solution is sufficient for maintaining patency of the central venous catheter, preventing the risks associated with heparin administration.

Co-stimulatory molecules are essential in the orchestration of immune response and polymorphisms in their genes are associated with various diseases. However, in the case of variable allele frequencies among continental populations, this variation can lead to biases in genetic studies conducted in admixed populations such as those from Brazil. The aim of this study was to evaluate the influence of genomic ancestry on distributions of co-stimulatory genes polymorphisms in an admixed Brazilian population. A total of 273 individuals from the north of Brazil participated in this study. Nine single nucleotide polymorphisms in 7 genes (CD28, CTLA4, ICOS, CD86, CD40, CD40L and BLYS) were determined by polymerase chain reaction-restriction fragment length polymorphism. We also investigated 48 insertion/deletion ancestry markers to characterize individual African, European and Amerindian ancestry proportions in the samples. The analysis showed that the main contribution was European (43.9%) but also a significant contribution of African (31.6%) and Amerindian (24.5%) ancestry. ICOS, CD40L and CD86 polymorphisms were associated with genomic ancestry. However there were no significant differences in the proportions of ancestry for the other SNPs and haplotypes studied. Our findings reinforce the need to apply AIMs in genetic association studies involving these polymorphisms in the Brazilian population., (Copyright © 2015 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Purpose: the main purpose of this study was to examine the relationship of body mass (BM) status with running and jumping performances in young male basketball players., Methods: basketball players (n=72, age 12.9±2.8 yrs), who were grouped into U-12 (9-12 yrs), U-15 (12-15 yrs) and U-18 (15-18 yrs), performed a battery of anthropometric, running and jumping tests. We examined differences among age groups, and between normal weight and overweight players., Results: the results indicated significant and large differences among age groups in BM, height, body mass index (BMI), fat mass (FM), fat-free mass, speed, endurance, standing long jump, countermovement jump (CMJ), mean power in 30 s jumping test (Pmean) (p<0.001, η(2)≥0.23) with older players presenting higher values. Within each age group, overweight players had higher BM, BMI, body fat percentage and FM (p<0.05) than their normal weight counterparts. Overweight players had worst performance in running (sprint and endurance) and jumping (CMJ and Pmean) in U-12, and worst endurance in U-18 (p<0.05, |d|≥0.82) than normal-weight players, whereas there was no difference in U-15., Conclusions: it was concluded that the relationship of BMI with running and jumping performances varied according to age. Based on these findings, trainers and coaches should focus on special intervention exercise and nutrition programs targeting optimal body mass especially in young basketball players, where the excess of body mass seemed to have the most detrimental effect on running and jumping performances.

In this work, we synthesize large-area thin films of a conjugated, imine-based, two-dimensional covalent organic framework at the solution/air interface. Thicknesses between ∼2-200 nm are achieved. Films can be transferred to any desired substrate by lifting from underneath, enabling their use as the semiconducting active layer in field-effect transistors.

Because of their extraordinary structural and electrical properties, two-dimensional materials are currently being pursued for applications such as thin-film transistors and integrated circuit. One of the main challenges that still needs to be overcome for these applications is the fabrication of air-stable transistors with industry-compatible complementary metal oxide semiconductor (CMOS) technology. In this work, we experimentally demonstrate a novel high performance air-stable WSe2 CMOS technology with almost ideal voltage transfer characteristic, full logic swing and high noise margin with different supply voltages. More importantly, the inverter shows large voltage gain (∼38) and small static power (picowatts), paving the way for low power electronic system in 2D materials.