bluuebunny/crossref_metadata_2025 huggingface dataset:
Bacterial pore‐forming toxin pneumolysin: Cell membrane structure and microvesicle shedding capacity determines differential survival of immune cell types
Authors: Larpin Yu , Besançon Hervé , Iacovache Mircea‐Ioan , Babiychuk Victoriia S. , Babiychuk Eduard B. , Zuber Benoît , Draeger Annette , Köffel René
Published: December 2019

Bacterial infectious diseases can lead to death or to serious illnesses. These outcomes are partly the consequence of pore‐forming toxins, which are secreted by the pathogenic bacteria (eg, pneumolysin of Streptococcus pneumoniae). Pneumolysin binds to cholesterol within the plasma membrane of host cells and assembles to form trans‐membrane pores, which can lead to Ca2+ influx and cell death. Membrane repair mechanisms exist that limit the extent of damage. Immune cells which are essential to fight bacterial infections critically rely on survival mechanisms after detrimental pneumolysin attacks. This study investigated the susceptibility of different immune cell types to pneumolysin. As a model system, we used the lymphoid T‐cell line Jurkat, and myeloid cell lines U937 and THP‐1. We show that Jurkat T cells are highly susceptible to pneumolysin attack. In contrast, myeloid THP‐1 and U937 cells are less susceptible to pneumolysin. In line with these findings, human primary T cells are shown to be more susceptible to pneumolysin attack than monocytes. Differences in susceptibility to pneumolysin are due to (I) preferential binding of pneumolysin to Jurkat T cells and (II) cell type specific plasma membrane repair capacity. Myeloid cell survival is mostly dependent on Ca2+ induced expelling of damaged plasma membrane areas as microvesicles. Thus, in myeloid cells, first‐line defense cells in bacterial infections, a potent cellular repair machinery ensures cell survival after pneumolysin attack. In lymphoid cells, which are important at later stages of infections, less efficient repair mechanisms and enhanced toxin binding renders the cells more sensitive to pneumolysin.
Early Childhood Development Caregiver Training and Neurocognition of HIV-Exposed Ugandan Siblings
Authors: Boivin Michael J. , Augustinavicius Jura L. , Familiar-Lopez Itziar , Murray Sarah M. , Sikorskii Alla , Awadu Jorem , Nakasujja Noeline , Bass Judith K.
Published: December 2019

Objective:

Early childhood development (ECD) programs can enhance neurocognitive development outcomes through caregiver training. This study explores whether school-age siblings benefited from a program provided to HIV-infected caregivers and their preschool-aged target children.

Methods:

Siblings of target 2- to 3-year-old children in ECD intervention households were evaluated at school age (5–12 years) on neurocognitive outcomes with the Kaufman Assessment Battery for Children (KABC), computerized Test of Variables of Attention, Behavior Rating Inventory for Executive Function (BRIEF; parent), and attention-deficit/hyperactivity disorder rating inventory (ADHD-R)-IV (parent). Households from 18 geographic clusters in eastern Uganda were randomized to individualized biweekly sessions of either (1) Mediational Intervention for Sensitizing Caregivers (MISC) training emphasizing cognitive stimulation/enrichment or (2) health/nutrition/development [Uganda Community-Based Association For Women & Children Welfare (UCOBAC)] program. Siblings with baseline and at least 1 follow-up assessment (n = 216) were included in the analysis. Three repeated postbaseline measures of sibling neurocognitive outcomes were analyzed using the linear mixed-effects model while adjusting for socioeconomic status and behavioral outcome at baseline.

Results:

Siblings in the MISC arm had better performance on KABC sequential processing at 6 months (p = 0.02) and simultaneous processing at 12 months (p = 0.03). MISC mothers rated their children as having significantly more problems on the BRIEF and ADHD-RS-IV (p < 0.01) than UCOBAC mothers across all time points.

Conclusion:

Mediational Intervention for Sensitizing Caregivers training resulted in some short-term neurocognitive benefits for school-aged siblings, but these differences were not sustained at 1-year follow-up. Exploring potential impacts of parenting programs on other children in the home is an important development for the field.
Erector Spinae Plane Block Decreases Pain and Opioid Consumption in Breast Surgery: Systematic Review
Authors: ElHawary Hassan , Abdelhamid Kenzy , Meng Fanyi , Janis Jeffrey E.
Published: December 2019

Background:

Adequate control of acute postoperative pain is crucial in breast surgeries, as it is a significant factor in the development of persistent chronic pain. Inadequate postoperative pain control increases length of hospital stays and risk of severe complications. Erector spinae plane block (ESPB) is a novel regional block that has the ability to sufficiently block unilateral multidermatomal sensation from T1 to L3. By reviewing the literature on ESPB, this paper aimed to elucidate its efficacy in breast surgery analgesia and its role in addressing the opioid crisis in North America.

Methods:

PUBMED, EMBASE, and Cochrane databases were systematically searched for relevant articles according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Inclusion criteria included any articles that described ESPB in breast surgery. Exclusion criteria composed of articles that exclusively discussed other kinds of regional blocks.

Results:

Thirty-two articles including 6 randomized controlled trials were included in this review. ESPB demonstrated superior pain control and less opioid consumption compared with tumescent anesthesia or using no block. However, ESPB showed lower efficacy in pain control compared with pectoral nerve block. Patients experienced less nausea and vomiting and were overall more satisfied with ESPB compared with other pain control modalities. The vast majority of the studies reported the ease of ESPB administration, and only 1 case presented with a complication.

Conclusions:

ESPB is a promising form of regional anesthesia that can decrease postoperative pain and opioid consumption when used as part of multimodal pain analgesia for patients undergoing breast surgery.
Application of Dermal Skin Substitutes for Hand and Finger Palmar Soft Tissue Loss
Authors: Lucas Dominique , Di Rocco Damien , Müller Camillo T. , Jurjus Abdo R. , Raffoul Wassim , di Summa Pietro G. , Watfa William
Published: December 2019

Restoring function after traumatic defects of the palm is a reconstructive challenge, considering the need for flexible, elastic, and resistant skin. Dermal skin substitutes are biologically engineered materials composed of collagen and glycosaminoglycan, devoid of cellular structures. These biodegradable materials act as artificial dermis and stimulate neovascularization: they have been used for many years, mainly on the dorsal side of the hand and fingers, whereas the palmar side of the hand has been generally addressed by local flaps. In this study, we described our experience with dermal skin substitutes in two cases of palmar defects associated with exposed tendinous structures. Coverage of palmar defects in hand and fingers with dermal substitute and split thickness skin graft was performed on two patients. Both patients presented palmar-only loss of tissue (traumatic palmar amputation in the first patient and degloving-type injury in the second patient). Range of motion, functional outcomes, and satisfaction and aesthetical results were evaluated. The resulting skin showed good quality, thickness, pliability, and Disabilities of the Arm, Shoulder, and Hand (DASH) score. Additionally, the patients regained full range of motion and reported high satisfaction. The association of split thickness skin graft with dermal substitutes in palmar traumatic hand showed optimal functional and aesthetic outcomes. Although being more adapted to dorsal loss of substance, collagen-based dermal substitutes can also be useful reconstructive tools in palmar defects with exposed structures and could be used to a larger extent in the future.
Control of the Suborbital Cheek in Pediatric Patients: Working in the Deep Plane
Authors: Salibian Ara A. , Zide Barry M.
Published: December 2019

Background:

Reconstruction of suborbital cheek and lower eyelid defects can be challenging in pediatric patients due to the need for lower eyelid support, lack of reliable local tissue, and difficulties of scar concealment. The deep-plane cervicofacial rotation-advancement flap is a useful technique for cheek reconstruction in adults; however, its utility in the pediatric population has not been described.

Methods:

Experience using the deep-plane Schrudde flap for large suborbital defects in pediatric patients is presented.

Results:

Safe flap elevation and successful reconstruction requires utilization of critical anatomic landmarks, a standardized sequence of dissection and appropriate fixation.
An Automated Telephone Call System Improves the Reach and Cost-effectiveness of Panel Management Outreach for Cancer Screening
Authors: Gagliardi Kristin S. , Coleman Sara , Intinarelli Gina , Karliner Leah , Appelle Nicole , Taylor Brian , Grumbach Kevin
Published: December 2019

This implementation and comparative effectiveness study compared an automated call system (ACS)-assisted method to enhance staff efficiency in panel management cancer screening outreach compared with standard outreach using manual calls. One panel manager assisted by the ACS at the intervention primary care practice completed outreach workflows for 43% more patients than 2 unassisted panel managers at comparison practices, with 78% more patients in the ACS-assisted panel management program ultimately having a preventive screening gap closed. Outreach cost per completion of 1 or more cancer screenings was $45.39 under standard procedures and $15.85 using the ACS-assisted method.
Rasch Analysis of the Global Appraisal of Individual Needs in the City of São Paulo
Authors: Claro Heloísa G. , Oliveira Márcia A. F. , Fernandes Ivan F. A. L. , Boska Gabriella de Andrade , dos Santos Nencis , Pinho Paula H. , Tarifa Rosana R. , Rojas Thais F. , Smith Douglas C.
Published: December 2019

Introduction

Approximately 5% of the global population used an illicit drug in 2013. Regarding licit drugs, alcohol is responsible for the occurrence of approximately 200 diseases, among them depression. In addition to health impairments, alcohol is also implicated in many acts of violence. This study aimed to measure the properties of the Rasch model of the Portuguese version of the Global Appraisal of Individual Needs-Short Screener based on evidence obtained during care for users of alcohol and other drugs.

Method

To collect the data, 128 interviews were held at the Psychosocial Care Center for Alcohol and Other Drugs in the state capital, during which the scale was applied.

Results

The Rasch model revealed that the subscales of the instrument were appropriate, with all items having mean infit and outfit values from 0.5 to 1.5, considered optimal for measurement. There was no evidence of differential performance for gender. Substance use and crime and violence items presented redundancy for severity measures.

Conclusion

Given the need for validated instruments for use in Brazil, it is encouraging that the Portuguese version of the scale was valid for the Rasch model. The results are consistent with studies using the other American, Brazilian, and Canadian versions of the instrument.
Omics in schizophrenia: current progress and future directions of antipsychotic treatments
Authors: Sun Yidan , Zhou Wei , Chen Luan , Huai Cong , Huang Hailiang , He Lin , Qin Shengying
Published: December 2019

Schizophrenia is a life-long, complex mental illness that still lacks satisfactory treatments. In recent years, increasing numbers of candidate biomarkers of schizophrenia occurrences and drug responses to schizophrenia therapies have been successfully identified by many omics studies. This review discusses the latest discoveries regarding effective drug targets and relevant drug classifications in schizophrenia. It also assesses our understanding of biomarkers for drug efficacy and adverse drug reactions in current schizophrenia treatments using omics technologies. Future applications in clinical practice have been proposed based on these new findings, and are now considered highly promising strategies to better treat schizophrenia. Finally, we explore several novel approaches that aim to reveal additional genetic signatures of schizophrenia using multi-omics data, which are hoped to improve the diagnosis and treatment of this illness in the future.
Prognostic value of neutrophil-to-lymphocyte ratio and its correlation with fluorine-18-fluorodeoxyglucose metabolic parameters in intrahepatic cholangiocarcinoma submitted to 90Y-radioembolization
Authors: Filippi Luca , Di Costanzo Giovan Giuseppe , Tortora Raffaella , Pelle Giuseppe , Saltarelli Adelchi , Marino Marsilia Giuseppina , Cianni Roberto , Schillaci Orazio , Bagni Oreste
Published: December 2019

Objective

The aim of this study was to investigate the prognostic value of neutrophil-to-lymphocyte ratio (NLR) and its relationship with several metabolic parameters obtained through PET in intrahepatic cholangiocarcinoma (ICC) submitted to radioembolization with 90Y-microspheres (90Y-radioembolization).

Methods

Records of 20 subjects affected by ICC and submitted to 90Y-radioembolization were retrospectively evaluated. In all cases, pretreatment NLR was carried out and fluorine-18-fluorodeoxyglucose (18F-FDG) PET/CT was acquired with the calculation of the following metabolic parameters: maximum and mean standardized uptake value (SUVmax and SUVmean), metabolic total volume and total lesion glycolysis. After 90Y-radioembolization, all patients underwent regular imaging and laboratory follow-up.

Results

All patients presented 18F-FDG-avid hepatic tumors at pretreatment PET/CT examination. NLR significantly correlated with SUVmax (r = 0.64; P = 0.002) and SUVmean (r = 0.67; P = 0.001). After treatment with 90Y-microspheres, the mean OS resulted 12.5 ± 1.5 months. When the average pretreatment NLR value (i.e. 2.7) was used as a cutoff for patients’ stratification, subjects with low NLR (<2.7) had a significantly longer OS than those with high NLR (>2.7). At Cox regression analysis including bilirubin, age, the presence of extrahepatic disease, hepatitis C virus/hepatitis B virus status and PET-derived parameters, only NLR resulted to be a significant predictor of OS (P = 0.01; hazard ratio = 13.1, 95% confidence interval = 1.6–102.7).

Conclusion

NLR is correlated with SUVmax-mean values in ICC and resulted to be an easy available predictor of survival in patients submitted to treatment with 90Y-microspheres.
Clinical characteristics of neuropathic pain in leprosy and associated somatosensory profiles: a deep phenotyping study in India
Authors: Haroun Omer M.O. , Vollert Jan , Lockwood Diana N. , Bennett David L.H. , Pai Vivek V. , Shetty Vanaja , Wakade Anju V. , Khodke Ashish S. , Schilder Andreas , Pfau Doreen , Enax-Krumova Elena K. , Maier Christoph , Treede Rolf-Detlef , Rice Andrew S.C.
Published: December 2019

This study investigated the clinical characteristics and somatosensory profiles of patients suffering from leprosy in Mumbai, India. A cross-sectional deep profiling study was conducted in 86 patients with leprosy (with and without pain) using an extensive battery of phenotyping measures including structured clinical examination, psychological state (General Health Questionnaire [GHQ-12]), and a quality-of-life condition-specific instrument (Brief Pain Inventory—short form). Quantitative sensory testing was performed according to the protocol of the German Research Network on Neuropathic Pain (DFNS) to assess the somatosensory profiles in the ulnar nerve innervation territory of all participants (dorsum of the hand). Reference data from 50 healthy Indian subjects were within the range of published DFNS values. Somatosensory profiles in leprosy patients with clinically or electroneurographically diagnosed neuropathy (with and without pain) revealed a profile of sensory loss to thermal and tactile stimuli combined with preservation of vibration and deep pressure detection. Sensory gain phenomena were not generally observed in patients with leprosy. In the group of subclinical neuropathy, a high degree of impaired thermal sensation was found, which could be clinically deployed to enhance identification of leprosy neuropathy at an early stage. Quantitative sensory testing can effectively document leprosy-associated neuropathy but does not distinguish between patients with or without pain. Patients with leprosy and neuropathic pain reported a poor quality of life and less psychological well-being compared with the pain-free patients with leprosy neuropathy.
A systematic review of western medicine's understanding of pain experience, expression, assessment, and management for Australian Aboriginal and Torres Strait Islander Peoples
Authors: Arthur Luke , Rolan Paul
Published: December 2019

Although pain is a near-universal experience, pain expression and beliefs are highly variable and can affect assessment and management of pain. This systematic review seeks to synthesize the research findings regarding pain management for Australian Aboriginal and Torres Strait Islander peoples addressing variation as voiced by patients, clinicians, and researchers alike. A systematic review was performed across 7 research databases for all articles related to pain within Indigenous Australian peoples. Additional literature was identified by hand-searching reference lists. Articles were restricted to literature which addressed pain within Indigenous Australians as the primary focus of the article. Thematic analysis was performed to group articles according to those which focussed on the experience, expression, assessment, or management of pain. A total of 294 articles were identified on initial search of literature, of which 20 met inclusion criteria for this study. This review captured gross heterogeneity in cohorts, research methodologies, and conditions studied, making generalized assumptions impossible and inappropriate. Studies suggest that the beliefs of both patients and practitioners are important considerations in approaching effective assessment and management of pain. Health practitioners should appreciate how our own beliefs influence the management of patients and must ensure community consultation is undertaken in order to improve pain assessment and management.
Prevalence of chronic pain in developing countries: systematic review and meta-analysis
Authors: Sá Katia Nunes , Moreira Larissa , Baptista Abrahão Fontes , Yeng Lin Tchia , Teixeira Manoel Jacobsen , Galhardoni Ricardo , de Andrade Daniel Ciampi
Published: December 2019

Chronic pain (CP) is prevalent worldwide. Current reports on its prevalence in developing countries are heterogeneous, and to date, there is no quantitative synthesis providing a general estimation of its magnitude in the developing world. The goal of this study was to estimate the pooled prevalence of CP in the general population in developing countries. This was a PROSPERO-registered CRD42019118680 systematic review including population-based cross-sectional studies on CP from countries with ≤0.8 human developing index. We calculated prevalence using both random effects and fixed effects. Heterogeneity was calculated by the Cochran Q test and the I2 statistic. Publication bias was evaluated by visual inspection of the Egger funnel plot, as well as by the Begg rank test and the Egger linear test. Sources of heterogeneity were also explored in subgroup analyses. Twelve studies with a total of 29,902 individuals were included in this meta-analysis, of which 7263 individuals were identified with CP. The overall pooled prevalence of CP after correction for publication bias was 18% (95% confidence interval: 10%–29%), the sample presenting significant heterogeneity (I2 = 100%, P < 0.001). Subgroup analyses demonstrated that year of publication and the adopted threshold for pain chronicity could partially explain the observed heterogeneity (P < 0.05). The proportion of individuals with CP in the general population of developing countries was 18%. However, reports of prevalence have high variability, especially related to year of publication and the threshold level adopted for pain chronicity.
An audit of paediatric pain prevalence, intensity, and treatment at a South African tertiary hospital
Authors: Velazquez Cardona Caridad , Rajah Chantal , Mzoneli Youley Nosisi , Friedrichsdorf Stefan Joerg , Campbell Fiona , Cairns Carel , Rodseth Reitze Nils
Published: December 2019

Introduction:

Pain in paediatric inpatients is common, underrecognised, and undertreated in resource-rich countries. Little is known about the status of paediatric pain prevention and treatment in low- and middle-income countries.

Objectives:

This audit aimed to describe the prevalence and severity of pain in paediatric patients at a tertiary hospital in South Africa.

Method:

A single-day prospective observational cross-sectional survey and medical chart review of paediatric inpatients at Grey's Hospital, Pietermaritzburg, South Africa.

Results:

Sixty-three children were included, and mean patient age was 9.7 years (SD 6.17). Most patients (87%) had pain during admission, with 29% reporting preexisting (possibly chronic) pain. At the time of the study, 25% had pain (median pain score 6/10). The worst pain reported was from needle procedures, including blood draws, injections, and venous cannulation (34%), followed by surgery (22%), acute illness/infection (18%), and other procedures (14%). Pharmacological treatments included WHO step 1 (paracetamol and ibuprofen) and step 2 (tramadol, tilidine, and morphine) analgesics. The most effective integrative interventions were distraction, swaddling, and caregiver participation. Although a pain narrative was present in the majority of charts, only 16% had documented pain intensity scores.

Conclusion:

The prevalence of pain in hospitalised children in a large South African Hospital was high and pain assessment inadequately documented. There is an urgent need for pain education and development of guidelines and protocols, to achieve better pain outcomes for children. This audit will be repeated as part of a quality-improvement initiative.
Analysis of Risk Factors Associated With Drooping Deformity After Lower Eyelid Reconstruction
Authors: Abe Yoshiro , Ishida Soushi , Mineda Kazuhide , Yamashita Yutaro , Yoshimoto Sho , Hashimoto Ichiro
Published: December 2019

Background

Lower eyelid reconstruction is challenging because of the risk of severe postreconstruction deformities of the lower eyelid, such as drooping, entropion, and ectropion. However, the risk factors for these postreconstruction deformities are unclear. The present study aimed to quantify the drooping deformity of the lower eyelid after reconstruction using a cheek rotation flap and to identify risk factors associated with postreconstruction deformities.

Methods

Our study group included 28 patients who underwent full-thickness lower eyelid reconstruction using a cheek rotation flap for anterior lamella reconstruction. We developed the drooping index to classify postreconstruction outcomes as good (index <1.2), fair (index between 1.2 and 1.5), and poor (index >1.5). We identified risk factors for a drooping deformity using univariate analyses (Mann-Whitney U or Spearman rank correlation, depending on data distribution).

Results

Overall, the drooping index ranged between 1.0 and 2.11, with an average value of 1.3. A good outcome was obtained in 11, a fair outcome in 12, and a poor outcome in 5 patients. Clinically severe ectropion was observed in five of the 17 patients in the fair and poor outcome groups, with four of these patients requiring revision surgery. Risk factors for postreconstruction drooping deformity included medial location of the tumor, resection involving more than 50% of the horizontal width of the lower eyelid, and dissection of subcutaneous tissue of the cheek extending below the zygomatic arch.

Conclusions

A cheek rotation flap provides satisfactory outcomes for full-thickness reconstruction of the lower eyelid. Extension of dissection of subcutaneous tissue of the cheek below the zygomatic arch increases the risk of postsurgical drooping deformity. Our drooping index provides a quantitative measure of drooping deformity and is clinically useful to classify outcomes.
Comparison of Nd:YAG Laser and Combined Intense Pulsed Light and Radiofrequency in the Treatment of Hypertrophic Scars
Authors: Khedr Mohamed M. , Mahmoud Wael Hussein , Sallam Fersan A. , Elmelegy Nader
Published: December 2019

Introduction

Hypertrophic scars are fibroproliferative disorders, seen after burn, trauma, and/or surgery. We aimed to compare the clinical and histopathological results of 1064-nm Nd:YAG laser and combined intense pulsed light and radiofrequency in the treatment of hypertrophic scars.

Methods

Fifty patients with hypertrophic scars were included in this prospective, randomized study. Twenty-five patients were treated with Nd:YAG laser and 25 patients with combined intense pulsed light and radiofrequency (E-light). The scars were evaluated at baseline, during and at 3 months after the final treatment session using the Vancouver scar scale. Biopsy specimens from scars were obtained before, during, and 3 months after the final treatment session and were stained with hematoxylin and eosin stain, Masson's trichrome stain, and immunostaining procedures for collagen I, collagen III, and TGF-β1.

Results

Significant improvements in the total Vancouver scar scale scores before and after the treatment in both groups (P< 0.001); however, a significant difference between both groups (P< 0.001), regarding the E-light, which showed better response than Nd:YAG laser. Hematoxylin and eosin and Masson's trichrome staining showed arrangement and thinning of collagen bundles and reduction in collagen density by in both groups, but the collagen bundles thinning and parallelism were more obvious in the E-light group. Significant decrease in the concentration of collagen I, collagen III, and TGF-β1 in the E-light group as compared with the laser group (P= 0.005,P= 0.003 andP< 0.001, respectively).

Conclusions

Both modalities were successful in the treatment of hypertrophic scars; however, a significant improvement in the clinical and histopathological findings was detected with the E-light method.
Clinical Importance and Risk Factors for Postoperative Late-Onset Pneumonia After Major Oral Cancer Surgery With Microvascular Reconstruction
Authors: Hsieh Yu-Hsuan , Kao Chia-Chen , Lin Cheng-Ta , Liu Wen-Chung , Yang Kuo-Chung , Ho Yen-Yi , Tsai Wei-Hsuan , Chen Lee-Wei
Published: December 2019

Background

Pulmonary complications are common among patients who have undergone major oral cancer surgery with microvascular reconstruction. Current literatures focused on early-onset pneumonia in the postoperative acute stage. In contrast, we are aiming to identify the clinical importance and the risk factors associated with late-onset pneumonia in oral cancer patients after acute stage.

Methods

In total, 195 patients were included from May 2014 to December 2016 and followed up for up to 1 year after surgery. Their medical histories were reviewed to identify the risk factors of late-onset pneumonia and outcome. Primary outcome was late-onset pneumonia. Other outcome measures included early-onset pneumonia, tumor recurrence, and death within 1 year after surgery.

Results

Patients with late-onset pneumonia have demonstrated a significantly higher rate of tumor recurrence (P < 0.001) and death within 1 year (P < 0.001). Independent risk factors of late-onset pneumonia identified were age (P = 0.031), previous radiotherapy (P = 0.017), postoperative radiotherapy (P = 0.002), flap size (P = 0.001), flap type other than osteocutaneous fibula flap (P = 0.009), and tumor recurrence (P < 0.001).

Conclusions

Late-onset pneumonia can act as a warning sign for oral cancer patients who have received microsurgical reconstruction, for its high correlation with tumor recurrence and mortality rate.
The past, present and future of cleaner fish cognitive performance as a function of CO2levels
Authors: Paula José Ricardo , Baptista Miguel , Carvalho Francisco , Repolho Tiago , Bshary Redouan , Rosa Rui
Published: December 2019

Ocean acidification is one of the many consequences of climate change. Various studies suggest that marine organisms' behaviour will be impaired under high CO2. Here, we show that the cognitive performance of the cleaner wrasse, Labroides dimidiatus, has not suffered from the increase of CO2from pre-industrial levels to today, and that the standing variation in CO2tolerance offers potential for adaptation to at least 750 µatm. We acclimated cleaners over 30 days to five levels of pCO2,from pre-industrial to high future CO2scenarios, before testing them in an ecologically relevant task—the ability to learn to prioritize an ephemeral food source over a permanent one. Fish learning abilities remained stable from pre-industrial to present-day pCO2. While performance was reduced under mid (750 µatm) and high CO2(980 µatm) scenarios, under the former 36% of cleaners still solved the task. The presence of tolerant individuals reveals potential for adaptation, as long as selection pressure on cognitive performance is strong. However, the apparent absence of high CO2tolerant fish, and potentially synergistic effects between various climate change stressors, renders the probability of further adaptation unlikely.
Sydney Percy Smith Andrew. 16 May 1926—2 November 2011
Authors: Davidson P. J. , Sharma M. M. , Davidson J. F.
Published: December 2019

Sydney Andrew was an outstanding chemical engineer. His career with ICI was notable, culminating in the rare distinction of appointment as senior research associate. Early work when he was a plant manager led to the development of a systematic procedure for plant maintenance, the forerunner of ‘critical path scheduling’, now widely used for planning complex construction and maintenance projects. Syd did pioneering work on the absorption of gases into liquids where the dissolved gas reacts with the liquid. He helped to develop catalysts for the steam reforming of naphtha, leading to the installation of many plants to provide gas for domestic use; these plants replaced the numerous plants for making town gas from coal. Producing syn-gas from naphtha was beneficial for making ammonia and methanol; several plants were built in India and Japan.
Behavioural analysis of single-cell aneural ciliate,Stentor roeseli,using machine learning approaches
Authors: Trinh Mi Kieu , Wayland Matthew T. , Prabakaran Sudhakaran
Published: December 2019

There is still a significant gap between our understanding of neural circuits and the behaviours they compute—i.e. the computations performed by these neural networks (Carandini 2012Nat. Neurosci.15, 507–509. (doi:10.1038/nn.3043)). Cellular decision-making processes, learning, behaviour and memory formation—all that have been only associated with animals with neural systems—have also been observed in many unicellular aneural organisms, namelyPhysarum,ParameciumandStentor(Tang & Marshall2018Curr. Biol.28, R1180–R1184. (doi:10.1016/j.cub.2018.09.015)). As these are fully functioning organisms, yet being unicellular, there is a much better chance to elucidate the detailed mechanisms underlying these learning processes in these organisms without the complications of highly interconnected neural circuits. An intriguing learning behaviour observed inStentor roeseli(Jennings 1902Am. J. Physiol. Legacy Content8, 23–60. (doi:10.1152/ajplegacy.1902.8.1.23)) when stimulated with carmine has left scientists puzzled for more than a century. So far, none of the existing learning paradigm can fully encapsulate this particular series of five characteristic avoidance reactions. Although we were able to observe all responses described in the literature and in a previous study (Dexteret al. 2019), they do not conform to any particular learning model. We then investigated whether models inferred from machine learning approaches, including decision tree, random forest and feed-forward artificial neural networks could infer and predict the behaviour ofS. roeseli. Our results showed that an artificial neural network with multiple ‘computational’ neurons is inefficient at modelling the single-celled ciliate's avoidance reactions. This has highlighted the complexity of behaviours in aneural organisms. Additionally, this report will also discuss the significance of elucidating molecular details underlying learning and decision-making processes in these unicellular organisms, which could offer valuable insights that are applicable to higher animals.
Vitamin D status in chronic tic-disorder and comorbid obsessive-compulsive disorder and attention-deficit/hyperactivity disorder: A pan-European study
Authors: Bond Molly , Moll Natalie , Rosello Alicia , Bond Rod , Schnell Jaana , Burger Bianka , Hoekstra Pieter J. , Dietrich Andrea , Schrag Anette , Kocovska Eva , Martino Davide , Mueller Norbert , Schwarz Markus , Meier Ute-Christiane ,   the EMTICS collaborative group
Published: December 2019

Background

Hypovitaminosis-D has been linked to neuropsychiatric conditions, but little is known about vitamin D status in individuals with chronic tic disorders (CTD). This study sought to determine whether vitamin D levels are associated with the severity of tics and presence and severity of comorbid obsessive-compulsive disorder (OCD) and/ or attention-deficit/hyperactivity disorder (ADHD).

Methods

This is a cross-sectional sub-study of the European Multicentre Tics in Children Studies (EMTICS). Vitamin D [25(OH)D] levels (ng/ml) were obtained for 327 participants with CTD at study entry and tic severity was measured using the Yale Global Tic Severity Scale (YGTSS). An association between tic severity and presence and severity of comorbid OCD and/or ADHD symptoms was analysed using multilevel models controlling for season, site, sex, age and presence of comorbid OCD and/or ADHD.

Results

The participants comprised 247 boys and 80 girls (4-16 years, mean [SD], 10.9 [2.72]). Hypovitaminosis-D ([25(OH)D] < 20ng/ml) was present in 33% of participants with CTD and/ or comorbid OCD and/ or ADHD. The authors found no association between 25(OH)D levels and tic severity or OCD symptom severity. However, lower 25(OH)D levels were significantly associated with increased severity of ADHD symptoms in participants with CTD (β = -0.25, s.e. = 0.08, 95% CI, -0.42 to -0.09; p < 0.01).

Conclusion

Additional research is needed to confirm these findings and assess whether hypovitaminosis-D may represent an underlying biological vulnerability for comorbid ADHD symptoms in CTD as it may signpost novel strategies for prevention and treatment.
Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys
Authors: Nagai Yuji , Miyakawa Naohisa , Takuwa Hiroyuki , Hori Yukiko , Oyama Kei , Ji Bin , Takahashi Manami , Huang Xi-Ping , Slocum Samuel T. , DiBerto Jeffrey F. , Xiong Yan , Urushihata Takuya , Hirabayashi Toshiyuki , Fujimoto Atsushi , Mimura Koki , English Justin G. , Liu Jing , Inoue Ken-ichi , Kumata Katsushi , Seki Chie , Ono Maiko , Shimojo Masafumi , Zhang Ming-Rong , Tomita Yutaka , Nakahara Jin , Suhara Tetsuya , Takada Masahiko , Higuchi Makoto , Jin Jian , Roth Bryan L. , Minamimoto Takafumi
Published: December 2019

The chemogenetic technology Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) affords remotely reversible control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, sluggish kinetics, metabolic liabilities, and potential off-target effects of CNO represent areas for improvement. Here we provide a new high affinity and selective agonist deschloroclozapine (DCZ) for muscarinic-based DREADDs. Positron emission tomography revealed that DCZ selectively bound to and occupied DREADDs in both mice and monkeys. Systemic delivery of low doses of DCZ (1 or 3 μg/kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 μg/kg) reversibly induced spatial working memory deficits in monkeys expressing hM4Di in the prefrontal cortex. DCZ represents the most potent, selective, metabolically stable and fast-acting DREADD agonist reported with utility in both mice and non-human primates for a variety of applications.
Position-sensing established during compaction dictates cell fate in the mammalian embryo
Authors: Royer Christophe , Leonavicius Karolis , Kip Annemarie , Fortin Deborah , Nandi Kirtirupa , Vincent Anna , Jones Celine , Child Tim , Coward Kevin , Graham Chris , Srinivas Shankar
Published: December 2019

Precise patterning within the 3-dimensional context of tissues, organs and embryos implies that cells can sense their relative position. We still understand relatively little about how cells sense their relative position within small groups of cells. During preimplantation development, outside and inside cells rely on apicobasal polarity and the Hippo pathway to choose their fate. Despite recent findings suggesting that mechanosensing may be central to this process, the relationship between blastomere geometry (i.e. shape and position) and the Hippo pathway effector YAP remains unknown. To address this, we used a highly quantitative approach to collect and analyse information on the geometry and YAP localisation of individual blastomeres of mouse and human embryos. We find that the fraction of YAP in the nucleus responds to the proportion of exposed cell surface area rather than blastomere shape. To directly test the influence of blastomere position on YAP localisation we developed an approach using hydrogel based cylindrical cavities to alter blastomere arrangement in cultured embryos. Unbiased clustering analyses of blastomeres from such embryos reveal that the ability to respond to position emerges as early as the 8-cell stage during compaction and that altering the relative position of a blastomere within an embryo can alter its fate. Finally, we demonstrate that this response is lost upon inhibiting PKC signalling, linking it to the cell polarity. Our results pinpoint when during early embryogenesis cell specification decisions are initiated and show how blastomeres can sense their position in a polarity dependent manner to alter YAP localisation.

Abstract Figure
Functional dissection of basal ganglia inhibitory input onto SNc dopaminergic neurons
Authors: Evans RC , Twedell EL , Zhu M , Ascencio J , Zhang R , Khaliq ZM
Published: December 2019

Substania nigra (SNc) dopaminergic neurons show a pause-rebound firing pattern in response to aversive events. Because these neurons integrate information from predominately inhibitory brain areas, it is important to determine which inputs functionally inhibit the dopamine neurons and whether this pause-rebound firing pattern can be produced by a solely inhibitory input. Here, we functionally map genetically-defined inhibitory projections from the dorsal striatum (striosome and matrix) and globus pallidus (GPe; parvalbumin and Lhx6) onto SNc neurons. We find that GPe and striosomal inputs both pause firing in SNc neurons, but rebound firing only occurs after inhibition from striosomes. Indeed, we find that striosomes are synaptically optimized to produce rebound and preferentially inhibit a subpopulation of ventral, intrinsically rebound-ready SNc dopaminergic neurons on their reticulata dendrites. Therefore, we describe a self-contained dendrite-specific striatonigral circuit that can produce pause-rebound firing in the absence of excitatory input.
High-throughput single-cell functional elucidation of neurodevelopmental disease-associated genes reveals convergent mechanisms altering neuronal differentiation
Authors: Lalli Matthew A. , Avey Denis , Dougherty Joseph D. , Milbrandt Jeffrey , Mitra Robi D.
Published: December 2019

The overwhelming success of exome- and genome-wide association studies in discovering thousands of disease-associated genes necessitates novel high-throughput functional genomics approaches to elucidate the mechanisms of these genes. Here, we have coupled multiplexed repression of neurodevelopmental disease-associated genes to single-cell transcriptional profiling in differentiating human neurons to rapidly assay the functions of multiple genes in a disease-relevant context, assess potentially convergent mechanisms, and prioritize genes for specific functional assays. For a set of 13 autism spectrum disorder (ASD) associated genes, we demonstrate that this approach generated important mechanistic insights, revealing two functionally convergent modules of ASD genes: one that delays neuron differentiation and one that accelerates it. Five genes that delay neuron differentiation (ADNP, ARID1B, ASH1L, CHD2, andDYRK1A) mechanistically converge, as they all dysregulate genes involved in cell-cycle control and progenitor cell proliferation. Live-cell imaging after individual ASD gene repression validated this functional module, confirming that these genes reduce neural progenitor cell proliferation and neurite growth. Finally, these functionally convergent ASD gene modules predicted shared clinical phenotypes among individuals with mutations in these genes. Altogether these results demonstrate the utility of a novel and simple approach for the rapid functional elucidation of neurodevelopmental disease-associated genes.
Monoubiquitination by the Fanconi Anemia core complex locks FANCI:FANCD2 on DNA in filamentous arrays
Authors: Tan Winnie , van Twest Sylvie , Leis Andrew , Bythell-Douglas Rohan , Murphy Vincent J. , Sharp Michael , Parker Michael W , Crismani Wayne M , Deans Andrew J.
Published: December 2019

FANCI:FANCD2 monoubiquitination is a critical event for replication fork stabilization by the Fanconi anemia (FA) DNA repair pathway. It has been proposed that at stalled replication forks, monoubiquitinated-FANCD2 serves to recruit DNA repair proteins that contain ubiquitin-binding motifs. Here we have reconstituted the FA pathwayin vitroto study functional consequences of FANCI:FANCD2 monoubiquitination. We report that monoubiquitination does not promote any specific exogenous protein:protein interactions, but instead stabilizes FANCI:FANCD2 heterodimers on dsDNA. This locking of FANCI:FANCD2 complex on DNA requires monoubiquitination of only the FANCD2 subunit. We further show that purified monoubiquitinated FANCI:FANCD2 forms filament-like arrays on long dsDNA using electron microscopy. Our results reveal how monoubiquitinated FANCI:FANCD2 is activated upon DNA binding and present new insights to potentially modulate monoubiquitinated FANCI:FANCD2/DNA filaments in FA cells.
Identification of HIV-1 Envelope Mutations that Enhance Entry Using Macaque CD4 and CCR5
Authors: Roop Jeremy I. , Cassidy Noah A. , Dingens Adam S. , Bloom Jesse D. , Overbaugh Julie
Published: December 2019

Although Rhesus macaques are an important animal model for HIV-1 vaccine development research, most transmitted HIV-1 strains replicate poorly in macaque cells. A major genetic determinant of this species-specific restriction is a non-synonymous mutation in macaque CD4 that results in reduced HIV-1 Envelope (Env)-mediated viral entry compared to human CD4. Recent research efforts employing either laboratory evolution or structure-guided design strategies have uncovered several mutations in Env’s gp120 subunit that enhance binding of macaque CD4 by transmitted/founder HIV-1 viruses. In order to identify additional Env mutations that promote infection of macaque cells, we utilized deep mutational scanning to screen thousands of Env point mutants for those that enhance HIV-1 entry via macaque receptors. We identified many uncharacterized amino acid mutations in the N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR) regions of gp41 that increased entry into cells bearing macaque receptors by up to 38-fold. Many of these mutations also modestly increased infection of cells bearing human CD4 and CCR5 (up to 13-fold). NHR/CHR mutations identified by deep mutational scanning that enhanced entry also increased sensitivity to neutralizing antibodies targeting the MPER epitope, and to inactivation by cold-incubation, suggesting that they promote sampling of an intermediate trimer conformation between closed and receptor bound states. Identification of this set of mutations can inform future macaque model studies, and also further our understanding of the relationship between Env structure and function.

Importance

Although Rhesus macaques are the favored non-human primate animal model used in HIV-1 research, most circulating HIV-1 strains poorly infect macaque cells. Studies using macaques to model HIV-1 infection often use evolved, or mutant HIV-1 variants that are able to utilize macaque CD4, but these HIV-1 variants poorly model infection by circulating strains. In this work, we sought to identity HIV-1 mutations that would allow entry into macaque cells, but that would maintain critical characteristics of circulating HIV-1 strains. We employed a powerful experimental method to simultaneously assess the effects of thousands of individual HIV-1 mutations on infection of cells bearing macaque receptors. We identified many previously uncharacterized mutations that enhance infection of circulating HIV-1 strains into cells bearing macaque receptors by up to 38-fold. Identification of these mutations may be of use in future macaque model studies.
SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine
Authors: Rothenburger Tamara , McLaughlin Katie-May , Herold Tobias , Schneider Constanze , Oellerich Thomas , Rothweiler Florian , Feber Andrew , Fenton Tim R. , Wass Mark N. , Keppler Oliver T. , Michaelis Martin , Cinatl Jindrich
Published: December 2019

The nucleoside analogue nelarabine, the prodrug of arabinosylguanine (AraG), has been known for decades to be effective against acute lymphoblastic leukaemias of T-cell (T-ALL), but not of B-cell (B-ALL) origin. The mechanisms underlying this lineage-specific drug sensitivity have remained elusive. Data from pharmacogenomics studies and from a panel of ALL cell lines revealed an inverse correlation of SAMHD1 expression and nelarabine sensitivity. SAMHD1 can hydrolyse and thus inactivate triphosphorylated nucleoside analogues. Transcriptomic and protein expression profiling of cell lines and patient-derived leukaemic blasts revealed lower SAMHD1 abundance in T-ALL than in B-ALL. Mechanistically, SAMHD1 promoter methylation strongly correlated with suppressed SAMHD1 expression, while T-ALL cells did not display increased global DNA methylation. Targeted SAMHD1 degradation using virus-like particles containing Vpx sensitised B-ALL cells to AraG, while ectopic SAMHD1 expression in SAMHD1-null T-ALL cells induced AraG resistance. SAMHD1 had a larger impact on cytarabine activity than on nelarabine/ AraG activity in acute myeloid leukaemia (AML) cells, but more strongly affected nelarabine/ AraG activity in ALL cells. This indicates a critical role of the cancer entity. In conclusion, lineage-specific differences in SAMHD1 promoter methylation and, in turn, SAMHD1 expression levels determine ALL cell response to nelarabine. SAMHD1 is a potential biomarker for the identification of ALL patients likely to benefit from nelarabine therapy and a therapeutic target to overcome nelarabine resistance.