bluuebunny/crossref_metadata_2025 huggingface dataset:
Combined Plasmatic and Tissue Approach to Membranous Nephropathy—Proposal of a Diagnostic Algorithm Including Immunogold Labelling: Changing the Paradigm of a Serum-based Approach
Authors: L’Imperio Vincenzo , Pieruzzi Federico G. , Sinico Renato A. , Nebuloni Manuela , Tosoni Antonella , Granata Antonio , Santoro Domenico , Capelli Irene , Garozzo Maurizio , Casano Stefano , Smith Andrew , Radice Antonella , Pagni Fabio
Published: March 2019

Membranous nephropathy represents the most frequent cause of nephrotic syndrome in the adult, leading to end-stage renal disease in one third of all the patients. In the last years, the discovery of circulating autoantibodies against phospholipase A2 receptor 1 (PLA2R) and thrombospondin type-1 containing 7A domain (THSD7A), shed light on the pathogenesis of idiopathic forms, being responsible for 70% and 3% of all the cases, respectively. These identifications allowed the development of serological and histologic tests to detect autoantibodies and relative targets for diagnostic and prognostic purposes. Rising evidences suggest that serum titer correlates with disease activity and response to therapy. For these reasons, for patients with nephrotic syndrome, a serum-based approach has been proposed, reserving renal biopsy only in cases with doubtful/negative serology. However, the recent introduction of useful criteria for the interpretation of PLA2R/THSD7A immunohistochemistry could lead to high values of sensitivity and specificity for the in situ detection of target antigens. The present multicentric study on a series of membranous nephropathy cases with available serum/histologic correlation will show the importance of the crosstalk among the different techniques, recovering the possible role of electron microscopy in challenging situations.
Expression of the Receptor for Hyaluronic Acid–Mediated Motility (RHAMM) in Endometrial Cancer is Associated With Adverse Histologic Parameters and Tumor Progression
Authors: Schatz-Siemers Nina , Chen Yao-Tseng , Chen Zhengming , Wang Dunrui , Ellenson Lora H. , Du Yi-Chieh Nancy
Published: March 2019

Endometrial cancer is one of the most common gynecologic malignancies worldwide. Only 2 agents have been approved by Food and Drug Administration for endometrial cancer since 1971. There is a need to identify molecular targets to treat advanced endometrial cancer. The receptor for hyaluronic acid–mediated motility (RHAMM) is upregulated in various types of cancer. Here, we aimed to determine the clinical significance of RHAMM expression in endometrial cancer. Two hundred twenty-five cases of endometrial cancer, including serous and endometrioid types, and 8 cases of normal endometrium were used for studying RHAMM protein levels. The Cancer Genome Atlas database was also queried for RHAMM mRNA expression in endometrial cancer. Increased expression of RHAMM protein was seen in endometrial cancer compared with no or weak expression in normal endometrium. RHAMM expression positively correlated with tumor grade. RHAMM expression was significantly increased in endometrial serous carcinomas, which are high-grade, aggressive types of endometrial cancer, compared with the relatively less aggressive endometrioid carcinomas. RHAMM expression also correlated with the presence of lymphovascular invasion. RHAMM mRNA expression correlated with decreased survival in The Cancer Genome Atlas cohort. Therefore, increased RHAMM expression in endometrial cancer is associated with high-grade tumors and is indicative of more aggressive behavior. These findings suggest RHAMM as a prognostic factor in endometrial cancer and as a potential therapeutic target in advanced endometrial cancer for future studies.
Motor Action Execution in Reaction-Time Movements
Authors: Tarkka Ina M. , Hautasaari Pekka
Published: March 2019

Objective

Reaction-time movements are internally planned in the brain. Presumably, proactive control in reaction-time movements appears as an inhibitory phase preceding movement execution. We identified the brain activity of reaction-time movements in close proximity to movement onset and compared it with similar self-paced voluntary movements without external command.

Design

We recorded 18 healthy participants performing reaction-time and self-paced fast index finger abductions with 306-sensor magnetoencephalography and electromyography. Reaction-time movements were performed as responses to cutaneous electrical stimulation delivered on the hand radial nerve area. Motor field and movement-evoked field 1 corresponding to the sensorimotor cortex activity during motor execution and afferent feedback after the movement were analyzed with Brainstorm's scouts using regions of interest analysis.

Results

Primary motor and somato sensory cortices were active before and after movement onset. During reaction-time movements, primary motor and somato sensory cortices showed higher activation compared with self-paced movements. In primary motor cortex, stronger preparatory activity was seen in self-paced than in reaction time task.

Conclusions

Both primary motor and somato sensory cortices participated in the movement execution and in the prediction of sensory consequences of movement. Cutaneous stimulation facilitated cortical activation during motor field after reaction-time movements, implying the applicability of cutaneous stimulation in motor rehabilitation.
Bone Marrow Mesenchymal Stem Cell Transplantation Enhances Nerve Regeneration in a Rat Model of Hindlimb Replantation
Authors: Abbas Ozan Luay , Özatik Orhan , Gönen Zeynep Burçin , Koçman Atacan Emre , Dağ Ilknur , Özatik Fikriye Yasemin , Bahar Dilek , Musmul Ahmet
Published: March 2019

Background:

Successful limb replantation must be based not only on the viability of the amputated part but also on satisfactory long-term functional recovery. Once the vascular, skeletal, and soft-tissue problems have been taken care of, nerve recovery becomes the ultimate limiting factor. Unfortunately, nerve regeneration after limb replantation is impaired by several consequences. The authors tested the hypothesis that bone marrow mesenchymal stem cells could improve nerve regeneration outcomes in an experimental model of limb replantation.

Methods:

Twenty rats underwent replantation after total hindlimb amputation. Animals were subdivided into two groups: a replanted but nontreated control group and a replanted and bone marrow mesenchymal stem cell–transplanted group. Three months after surgery, nerve regeneration was assessed using functional, electrophysiologic, histomorphologic, and immunohistochemical analyses.

Results:

Bone marrow mesenchymal stem cell–treated animals showed significantly better sciatic functional index levels and higher compound muscle action potential amplitudes in comparison with the controls. Histomorphometric analysis revealed that the number of regenerating axons was approximately two-fold greater in the treated nerves. In addition, the mean g-ratio of these axons was within the optimal range. Immunohistochemical assessment revealed that expression of S-100 and myelin basic protein in the treated nerves was significantly higher than in controls. Correspondingly, the expression levels of anti–protein gene product 9.5 and vesicular acetylcholine transporter in motor endplates were also significantly higher. Finally, muscles in the bone marrow mesenchymal stem cell–transplanted group showed significantly larger average fiber areas.

Conclusion:

The authors’ findings demonstrate that it is possible to improve the degree of nerve regeneration after limb replantation by bone marrow mesenchymal stem cell transplantation.
Routine Postoperative Admission to the Intensive Care Unit Following Repair of Nonsyndromic Craniosynostosis: Is it Necessary?
Authors: Chocron Yehuda , Azzi Alain , Galli Rafael , Alnaif Nayif , Atkinson Jeffrey , Dudley Roy , Farmer Jean-Pierre , Gilardino Mirko S.
Published: March 2019

Background:

Cranial vault surgery for craniosynostosis is generally managed postoperatively in the intensive care unit (ICU). The purpose of the present study was to examine our center's experience with the postoperative management of otherwise healthy patients with nonsyndromic craniosynostosis (NSC) without routine ICU admission.

Methods:

A retrospective cohort study of patients with NSC operated using a variety of vault reshaping techniques in our pediatric center between 2009 and 2017 was carried out. Patients with documented preexisting comorbidities that would have required admission to the ICU regardless of the surgical intervention were excluded.

Results:

A total of 102 patients were included in the study. Postoperatively, 100 patients (98%) were admitted as planned to a general surgical ward following observation in the recovery room. Two patients (2%) required ICU admission due to adverse intraoperative events. There were no patients who required transfer to the ICU from the recovery area or surgical ward. Within the surgical ward cohort, 6 patients (6%) had minor postoperative complications that were readily managed on the surgical floor. Postoperative anemia requiring transfusion was the most common complication.

Conclusion:

The results from this study suggest that otherwise healthy patients with NSC undergoing cranial vault surgery can potentially be safely managed without routine admission to the ICU postoperatively. Key elements are proper preoperative screening, access to ICU should an adverse intraoperative event occur and necessary postoperative surgical care. The authors hope that this experience will encourage other craniofacial surgeons to reconsider the dogma of routine ICU admission for this patient population.
Toothache as a Warning Sign of Subarachnoid Hemorrhage Postmortem Findings
Authors: Xingang Qiu , Wang Xian , Meichen Pan , Yuning Wang , Qian Liu
Published: March 2019

The symptoms of sudden severe headache and/or diminished consciousness characterize the onset of aneurysmal subarachnoid hemorrhage (SAH). However, several studies have suggested that some patients show an atypical presentation at the onset: symptoms lacking sudden headache and diminished consciousness. These atypical symptoms can easily lead to misdiagnosis. This paper reported the death cases of acute aneurysmal subarachnoid hemorrhage with toothache as the first symptom, hoping to provide clinical evidence for the general public doctors to reduce the misdiagnosis and delayed diagnosis of SAH, improve the identification ability of SAH, and prevent such death events from happening again.
Better Function With a Colonic J-Pouch or a Side-to-end Anastomosis?
Authors: Parc Yann , Ruppert Reinhard , Fuerst Alois , Golcher Henriette , Zutshi Massarat , Hull Tracy , Tiret Emmanuel , Hemminger Felix , Galandiuk Susan , Fender Svenja , Weber Klaus , Zimmerman Anton , Aiello Alexandra , Fazio Victor
Published: March 2019

Background information:

We aimed to compare prospectively the complications and functional outcome of patients undergoing a J-Pouch (JP) or a side-to-end anastomosis (SE) for treatment of low rectal cancer at a 2-year time point after resection for rectal cancer.

Methods:

A multicenter study was conducted on patients with low rectal cancer who were randomized to receive either a JP or SE and were followed for 24 months utilizing SF-12 and FACT-C surveys to evaluate the quality of life (QOL). Fecal incontinence was evaluated using the Fecal Incontinence Severity Index (FISI). Bowel function, complications, and their treatments were recorded.

Results:

Two hundred thirty-eight patients (165 males) were randomized with 167 final eligible patients, 80 in the JP group and 87 in the SE group for evaluation. The mean age at surgery was 61 (range 29 to 82) years. The overall mean recurrence rate was 12 of 238, 5% and similar in both groups.

Complications:

Overall, 37 of 190 (19%) patients reported complications, 14 of these were Clavien Dindo Grade 3b and 2 were 3a: leak 3 (2 JP,1 SE), fistula 4 (1 JP, 3 SE), small bowel obstruction 4 (3JP, 1 SE), stricture 4 (3 SE, 1 SA), pouch necrosis 2 (JP), and wound infection 5 (2 JP, 3 SE). QOL scores using either instrument between the 2 groups at 12 and 24 months were similar (P > 0.05). Bowel movements, clustering, and FISI scores were similar.

Conclusion:

At time points of 1 and 2 years after a JP or a SE for low rectal cancer, QOL, functional outcome, and complications are comparable between the groups. Although choosing a particular procedure may depend on surgeon/patient choice or anatomical considerations at the time of surgery, SE functions similar to JP and may be chosen due to the ease of construction.
A Systematic Review and Meta-analysis on Omentoplasty for the Management of Abdominoperineal Defects in Patients Treated for Cancer
Authors: Blok Robin D. , Hagemans Jan A. W. , Klaver Charlotte E. L. , Hellinga Joke , van Etten Boudewijn , Burger Jacobus W. A. , Verhoef Cornelis , Hompes Roel , Bemelman Wilhelmus A. , Tanis Pieter J.
Published: March 2019

Objective:

The objective of this systematic review and meta-analysis was to examine the effects of omentoplasty on pelviperineal morbidity following abdominoperineal resection (APR) in patients with cancer.

Background:

Recent studies have questioned the use of omentoplasty for the prevention of perineal wound complications.

Methods:

A systematic review of published literature since 2000 on the use of omentoplasty during APR for cancer was undertaken. The authors were requested to share their source patient data. Meta-analyses were conducted using a random-effects model.

Results:

Fourteen studies comprising 1894 patients (n = 839 omentoplasty) were included. The majority had APR for rectal cancer (87%). Omentoplasty was not significantly associated with the risk of presacral abscess formation in the overall population (RR 1.11; 95% CI 0.79–1.56), nor in planned subgroup analysis (n = 758) of APR with primary perineal closure for nonlocally advanced rectal cancer (RR 1.06; 95% CI 0.68–1.64). No overall differences were found for complicated perineal wound healing within 30 days (RR 1.30; 95% CI 0.92–1.82), chronic perineal sinus (RR 1.08; 95% CI 0.53–2.20), and pelviperineal complication necessitating reoperation (RR 1.06; 95% CI 0.80–1.42) as well. An increased risk of developing a perineal hernia was found for patients submitted to omentoplasty (RR 1.85; 95% CI 1.26–2.72). Complications related to the omentoplasty were reported in 4.6% (95% CI 2.5%–8.6%).

Conclusions:

This meta-analysis revealed no beneficial effect of omentoplasty on presacral abscess formation and perineal wound healing after APR, while it increases the likelihood of developing a perineal hernia. These findings do not support the routine use of omentoplasty in APR for cancer.
Retired Surgeons as Mentors for Surgical Training Graduates Entering Practice
Authors: Kim Na Eun , Moseley Jennifer M. , O’Neal Patrick , Whang Edward , Itani Kamal M. F. , Kristo Gentian
Published: March 2019

Objective:

Our study evaluated the willingness of retired surgeons to mentor newly trained surgeons.

Summary Background Data:

Although mentoring is very important during the transition in practice, many novice surgeons are faced with inadequacy or lack of mentoring.

Methods:

A survey regarding mentorship of new surgeons was sent in April 2018 to retired general, colorectal, vascular, and cardiothoracic surgeons that are members of the American College of Surgeons. The analysis of the data was performed in September 2018 and October 2018.

Results:

A total of 2295 of 5282 surveys were completed (43.4% response rate). Mean age was 79.0 ± 0.8 years, mean retirement age was 63.9 ± 0.1 years, and mean interval since retirement was 15.2 ± 0.9 years. Most retired surgeons were in private practice (66.4%), with other practice environments, including academic teaching hospital (12%), academic/private combination (11.3%), employment by community hospital or health system (6.4%), veteran affairs institution (2.7%), military hospital (1%), and Indian Health Service (0.09%). Approximately a third (31.1%) of respondents were not mentored when they first entered practice. The vast majority (98.3%) of participants considered mentoring beneficial during transition in practice. More than half (51.2%) of retired surgeons are interested in mentoring recently trained surgeons, with most of them (81.8%) willing to mentor even for free.

Conclusion:

Our findings suggest that a significant number of retired surgeons are enthusiastic about mentoring young surgeons during their transition in practice. Specific programs are necessary to meet the needs of newly hired surgeons and better utilize the expertise of retired surgeons.
The Association Between Pelvic Floor Muscle Force and General Strength and Fitness in Postpartum Women
Authors: Moss Whitney , Shaw Janet M. , Yang Meng , Sheng Xiaoming , Hitchcock Robert , Niederauer Stefan , Packer Diane , Nygaard Ingrid E.
Published: March 2019

Objective

The aim of the study was to determine whether measures of muscular strength and fitness are associated with pelvic floor muscle (PFM) force 1-year postpartum in a population of primiparous women who delivered vaginally.

Methods

This cross-sectional analysis is an ancillary study to an ongoing prospective cohort study and includes 203 primiparous women. Procedures collected 1-year postpartum included maximal PFM force, grip strength, trunk flexor muscle endurance, percent body fat, intra-abdominal pressure during trunk flexor endurance testing, intra-abdominal pressure during strain, and self-reported physical activity.

Results

The mean (SD) age was 29.8 (5.0) years and the mean (SD) body mass index was 24.5 (5.2) kg/m2. Nineteen percent were of Hispanic ethnicity. The median (interquartile range) PFM force was 5.05 (2.86–7.94) N. The median (interquartile range) trunk flexor endurance time was 146.0 (78.0–267.0), whereas the mean (SD) grip strength and percent fat were 32.4 (6.4) kg and 29.4% (10.0), respectively.

There were no statistically significant associations between PFM force and any of the measures tested on analyses unadjusted or adjusted for self-report of doing PFM exercises. Of other factors evaluated, non-Hispanic ethnicity, increasing age, self-reported family history of pelvic organ prolapse or urinary incontinence, and normal and obese body mass index (both compared with overweight) were associated with lower PFM force.

Conclusions

In primiparous women 1-year postpartum, we found no associations between PFM force and measures of strength and fitness. This study’s results are consistent with existing literature that specific, targeted, and consistent pelvic floor exercises are the best way to improve PFM strength.
Nortriptyline Abuse: A Case Report and Review of the Literature
Authors: Miller John Jeffrey , Whiting William L. , Catalano Glenn , Sanchez Deborah L.
Published: March 2019

The tricyclic antidepressants have long been a tool in the physician's armament for numerous indications, the most prominent of which being depression. Although their efficacy and side effects have been well documented, less known is their abuse. Prior literature has discussed this more for the tertiary amines such as amitriptyline, but currently, there are no documented cases of abuse with the secondary amine nortriptyline. This article reviews the prior literature in regard to tricyclic antidepressants and anticholinergics as substances of abuse, the proposed mechanisms of this, and susceptible populations, as well as a case review of a patient who admitted to using nortriptyline for its “buzz.”
Cessation of Skin Picking Symptoms With Methylphenidate Treatment in a Child With Comorbid Skin Picking and Attention-Deficit/Hyperactivity Disorder
Authors: Çolak Sivri Rukiye , Çolak Burçin
Published: March 2019

Skin picking disorder includes behaviors such as picking, scratching, and squeezing of the normal skin in an impulsive, repetitive manner despite the fact that no dermatological condition is detected. Skin picking disorder may also be comorbid in children with attention-deficit/hyperactivity disorder (ADHD) and vice versa. There is a great deal of data regarding the efficacy and safety of methylphenidate (MPH) treatment of ADHD. In this article, we report the cessation of skin picking behaviors in a 10-year-old girl diagnosed as having skin picking disorder and ADHD after modified-release MPH treatment. To our knowledge, this is the first case report that shows the cessation of skin picking behavior after MPH treatment in a child with ADHD.
Factors Associated With Delirium in Surgical Intensive Care Unit Patients Treated With Supplemental Melatonin: A Case-Cohort Study
Authors: Cusimano Joseph M. , Welch Sarah , Perez-Protto Silvia , Lam Simon
Published: March 2019

Objectives

Intensive care unit (ICU) delirium is a common neuropsychiatric syndrome that confers significant morbidity and mortality. Melatonin is an endogenous neurohormone involved with regulating sleep-wake cycles and has been found to be disturbed in ICU delirium. We hypothesized that there are independent factors that predict delirium in a cohort of patients on melatonin in the surgical ICU (SICU).

Methods

A retrospective, observational case-cohort analysis of adult SICU patients was conducted. Cases were defined by testing positive on the Confusion Assessment Method for the ICU (CAM-ICU). Delirioprotective and deliriogenic factors were assessed prior to the studied melatonin administration.

Results

Forty-one CAM-ICU–positive cases and 59 CAM-ICU–negative controls were included. Higher mean Acute Physiology and Chronic Health Evaluation II scores were associated with delirium in univariable analysis. Stratified analysis found a higher incidence of delirium in baseline CAM-ICU–positive patients who experienced emergency surgery within 24 hours of admission compared with baseline CAM-ICU–negative patients after melatonin administration.

Conclusions

This study describes the use of melatonin in the SICU and characterizes the patients who receive it. Further research is needed to determine the role of melatonin in deliriogenesis and to clarify its utility as a delirioprotectant for postsurgical, critical care patients.
Reinforcement regulates timing variability in thalamus
Authors: Wang Jing , Hosseini Eghbal , Meirhaeghe Nicolas , Akkad Adam , Jazayeri Mehrdad
Published: March 2019

Learning reduces variability but variability can facilitate learning. This paradoxical relationship has made it challenging to tease apart sources of variability that degrade performance from those that improve it. We tackled this question in a context-dependent timing task requiring humans and monkeys to flexibly produce different time intervals with different effectors. Subjects’ timing variability featured two novel and context-specific sources of variability: (1) slow memory-contingent fluctuations of the mean that degraded performance, and (2) fast reinforcement-dependent regulation of variance that improved performance. Signatures of these processes were evident across populations of neurons in multiple nodes of the cortico-basal ganglia circuits. However, only in a region of the thalamus involved in flexible control of timing were the slow performance-degrading fluctuations aligned to performance-optimizing regulation of variance. These findings provide direct evidence that the nervous system makes strategic use of exploratory variance to guard against other undesirable sources of variability.
Food Webs: Insights from a General Ecosystem Model
Authors: Flores Cesar O. , Kortsch Susanne , Tittensor Derek , Harfoot Mike , Purves Drew
Published: March 2019

Food webs have been intensively studied throughout modern ecology, using empirical evidence, statistics and modelling tools to search for consistent patterns, underlying commonalities, and variations between food webs and ecosystems. However, with few exceptions, the modelling approaches have not been based on the emergent properties of complex simulated ecosystems. For the same reason, there have also been few studies of ‘sampling the model’, in which different levels of sampling effort are imposed in a controlled simulated environment to explore the effects of varying sampling intensity in order to relate those back to empirical observations. Here, we introduce the Madingley Model, a general ecosystem model based on ecological and biological first principles of interactions between individuals, as a potential tool for analyzing food webs. In doing so, we present the first insights of the analyses of emergent Madingley food web networks. We describe the basic structure of these networks and introduce a process to aggregate and sample the food webs produced by this model so that it can be compared to empirical food web studies. We show that food webs created by this model reasonably reproduce the properties of empirical food web networks. Furthermore, we provide insights about the effects of species aggregation and sampling on the observed structure of empirically documented food webs.
The value of what’s to come: neural mechanisms coupling prediction error and reward anticipation
Authors: Iigaya Kiyohito , Hauser Tobias U. , Kurth-Nelson Zeb , O’Doherty John P. , Dayan Peter , Dolan Raymond J.
Published: March 2019

Having something to look forward to is a keystone of well-being. Anticipation of a future reward, like an upcoming vacation, can often be more gratifying than the very experience itself. Theories of anticipation have described how it induces behaviors ranging from beneficial information-seeking through to harmful addiction. However, it remains unclear how neural systems compute an attractive value from anticipation, instead of from the reward itself. To address this gap, we administered a decision-making task to human participants that allowed us to analyze brain activity during receipt of information predictive of future pleasant outcomes. Using a computational model of anticipatory value that captures participants’ decisions, we show that an anticipatory value signal is orchestrated by influences from three brain regions. Ventromedial prefrontal cortex (vmPFC) tracks the value of anticipation; dopaminergic midbrain responds to information that enhances anticipation, while sustained hippocampal activity provides a functional coupling between these regions. This coordinating function of the hippocampus is consistent with its known role in episodic future thinking. Our findings shed new light on the neural underpinnings of anticipation’s influence over decision-making, while also unifying a range of phenomena associated with risk and time-delay preference.
Inter-membrane association of the Sec and BAM translocons for bacterial outer-membrane biogenesis
Authors: Alvira Sara , Watkins Daniel W. , Troman Lucy , Allen William J. , Lorriman James , Degliesposti Gianluca , Cohen Eli J. , Beeby Morgan , Daum Bertram , Gold Vicki A.M. , Skehel J. Mark , Collinson Ian
Published: March 2019

The outer-membrane of Gram-negative bacteria is critical for surface adhesion, pathogenicity, antibiotic resistance and survival. The major constituent – hydrophobic β-barrelOuter-MembraneProteins (OMPs) – are secreted across the inner-membrane through the Sec-translocon for delivery to periplasmic chaperonese.g.SurA, which prevent aggregation. OMPs are then offloaded to the β-BarrelAssemblyMachinery (BAM) in the outer-membrane for insertion and folding. We show theHolo-TransLocon (HTL: an assembly of the protein-channel core-complex SecYEG, the ancillary sub-complex SecDF, and the membrane ‘insertase’ YidC) contacts SurA and BAM through periplasmic domains of SecDF and YidC, ensuring efficient OMP maturation. Our results show the trans-membrane proton-motive-force (PMF) acts at distinct stages of protein secretion: for SecA-driven translocation across the inner-membrane through SecYEG; and to communicate conformational changesviaSecDF to the BAM machinery. The latter presumably ensures efficient passage of OMPs. These interactions provide insights of inter-membrane organisation, the importance of which is becoming increasingly apparent.
Effect of READ1 on latent profiles of reading disability and comorbid attention and language learning disability subtypes
Authors: Li Miao , Truong Dongnhu T. , DeMille Mellissa , Malins Jeffrey G. , Lovett Maureen W. , Bosson-Heenan Joan , Gruen Jeffrey R. ,   on behalf of the Genes, Reading, and Dyslexia Study, Frijters Jan C.
Published: March 2019

Recent studies of co-occurring reading disability (RD) and attention deficit/hyperactivity disorder (ADHD), and co-occurring RD and language learning disability (LLD), support a core disability plus co-occurrence model focused on language and attention. Genetic factors have been associated with poor reading performance. However, little is known about whether different genetic variants independently contribute to RD co-occurrence subtypes. We aimed to identify subgroups of struggling readers using a latent profile analysis (LPA) in a sample of 1,432 Hispanic American and African American youth. RD classes were then tested for association with variants of READ1, a regulatory element within the candidate RD risk gene,DCDC2. Six groups were identified in the LPA using RD designation as a known-class variable. The three RD classes identified groups of subjects with neurocognitive profiles representing RD+ADHD, specific phonological deficit RD, and RD+LLD. Genetic associations across RD subtypes were investigated against functional groupings of READ1. The RU1-1 group of READ1 alleles was associated with RD cases that were marked by deficits in both processing speed and attention (RD + ADHD). TheDCDC2microdeletion that encompasses READ1 was associated with RD cases showing a phonological deficit RD profile. These findings provide evidence for differential genetic contribution to RD subtypes, and that previously implicated genetic variants for RD may share an underlying genetic architecture across population groups for reading disability.
Using the past to estimate sensory uncertainty
Authors: Beierholm Ulrik , Rohe Tim , Ferrari Ambra , Stegle Oliver , Noppeney Uta
Published: March 2019

To form the most reliable percept of the environment, the brain needs to represent sensory uncertainty. Current theories of perceptual inference assume that the brain computes sensory uncertainty instantaneously and independently for each stimulus.

In a series of psychophysics experiments human observers localized auditory signals that were presented in synchrony with spatially disparate visual signals. Critically, the visual noise changed dynamically over time with or without intermittent jumps. Our results show that observers integrate audiovisual inputs weighted by sensory reliability estimates that combine information from past and current signals as predicted by an optimal Bayesian learner or approximate strategies of exponential discounting

Our results challenge classical models of perceptual inference where sensory uncertainty estimates depend only on the current stimulus. They demonstrate that the brain capitalizes on the temporal dynamics of the external world and estimates sensory uncertainty by combining past experiences with new incoming sensory signals.
Parasites Acquired Beta Satellite DNAs from Hominid Hosts via Horizontal Gene Transfer
Authors: Yang Jiawen , Zhou Yiting , Ma Guangwei , Zhang Xueyan , Guo Yabin
Published: March 2019

Beta satellite DNA (satDNA) sequences are repeated DNA elements located in primate centromeres and telomeres, and might play roles in genome stability and chromosome segregation. Beta satDNAs mainly exist in great apes. Previous studies suggested that beta satDNAs may originate in old world monkeys. In this study, we searched both GenBank and SRA database, and identified beta satDNA sequences from the genomic sequences of 22 species. The beta satDNA sequences found in Prosimian, Dermoptera and Scandentia indicated that the origin of beta satDNAs might be as early as 80 MYA. Strikingly, beta satDNA sequences were also found in a number of some species evolutionarily far from primates, including several endoparasites of human and other great apes, which could be the results of multiple horizontal gene transfer (HGT) events. The similar phylogenic profiles between beta satDNAs in the parasite genomes and the human genome indicates that the parasite beta satDNAs have undergone similar concerted evolution and play similar roles as the beta satDNAs in primates.

Highlights

The ever largest scale analysis on beta satDNAs.

The origin of beta satDNAs was traced back to ∼80 MYA.

Mass existence of beta satDNAs in non-primate species was contributed by multiple HGT events.
Anophelesbionomics, insecticide resistance mechanisms and malaria transmission in the Korhogo area, northern Côte d’Ivoire: a pre-intervention study
Authors: Zogo Barnabas , Soma Dieudonné Diloma , Tchiekoi Bertin N’Cho , Somé Anthony , Alou Ludovic P. Ahoua , Koffi Alphonsine A. , Fournet Florence , Dahounto Amal , Coulibaly Baba , Kandé Souleymane , Dabiré Roch Kounbobr , Baba-Moussa Lamine , Moiroux Nicolas , Pennetier Cédric
Published: March 2019

Background

A better understanding of malaria transmission at a local scale is essential for developing and implementing effective control strategies. In the frame of a randomized control trial, we aimed to provide an updated description of malaria transmission in the Korhogo area, northern Côte d’Ivoire, and to get baseline data for the trial.

Methods

We performed Human Landing Collections in 26 villages in the Korhogo area during the rainy season (September-October 2016, April-May 2017) and the dry season (November-December 2016, February-March 2017). We used Polymerase chain reaction techniques to ascertain the species of theAn. gambiaecomplex,Plasmodium spsporozoite infection and insecticide resistance mechanisms in a subset ofAnophelesvectors.

Results

Anopheles gambiae s.l. was the predominant malaria vector in the Korhogo area. Overall, more vectors were collected outdoors than indoors (P < 0.001). Of the 774An. gambiae s.l. tested in the laboratory, 89.65% wereAn. gambiae s.s. and 10.35% wereAn. coluzzii. The frequencies of thekdrallele were very high inAn. gambiae s.s. but theace-1allele was found at moderate frequencies. An unprotected individual living in the Korhogo area received an average of 9.04, 0.63, 0.06 and 0.12 infected bites per night in September-October, November-December, February-March, and April-May, respectively.

Conclusions

The intensity of malaria transmission is extremely high in the Korhogo area, especially during the rainy season. Malaria control in highly endemic areas such as Korhogo needs to be strengthened with complementary tools in order to reduce the burden of the disease.
Detection and characterization of apoptotic and necrotic cell death by time-lapse quantitative phase image analysis
Authors: Vicar Tomas , Raudenska Martina , Gumulec Jaromir , Masarik Michal , Balvan Jan
Published: March 2019

Cell viability and cytotoxicity assays are highly important for drug screening and cytotoxicity tests of antineoplastic or other therapeutic drugs. Even though biochemical-based tests are very helpful to obtain preliminary preview, their results should be confirmed by methods based on direct cell death assessment. In this study, time-dependent changes in quantitative phase-based parameters during cell death were determined and methodology useable for rapid and label-free assessment of direct cell death was introduced. Our method utilizes Quantitative Phase Imaging (QPI) which enables the time-lapse observation of subtle changes in cell mass distribution. According to our results, morphological and dynamical features extracted from QPI micrographs are suitable for cell death detection (76% accuracy in comparison with manual annotation). Furthermore, based on QPI data alone and machine learning, we were able to classify typical dynamical changes of cell morphology during both caspase 3,7-dependent and independent cell death subroutines. The main parameters used for label-free detection of these cell death modalities were cell density (pg/pixel) and average intensity change of cell pixels further designated as Cell Dynamic Score (CDS). To the best of our knowledge, this is the first study introducing CDS and cell density as a parameter typical for individual cell death subroutines with prediction accuracy 75.4 % for caspase 3,7-dependent and -independent cell death.
Contribution of PSD-95 protein to reward location memory
Authors: Cały Anna , Śliwińska Małgorzata Alicja , Ziółkowska Magdalena , Łukasiewicz Kacper , Pagano Roberto , Nowacka Agata , Borczyk Malgorzata , Radwanska Kasia
Published: March 2019

The molecular mechanisms involved in formation of memory are still poorly understood. We focus here on the function of post-synaptic density protein 95 (PSD-95) and its phosphorylation by CaMKII in spontaneous learning about reward location in female mice. We show that formation of reward location memory leads to downregulation of PSD-95 protein in dendritic spines of thestratum radiatum, area CA1, and selective shrinkage of dendritic spines that contain PSD-95. ShRNA-driven, long-term downregulation of PSD-95 in the area CA1 decreases precision of memory. Autophosphorylation deficient CaMKII mutant mice (CaMKII:T286A) need more time than wild-type animals to learn the location of reward. The same impairment is observed after CA1-targeted overexpression of CaMKII phosphorylation-deficient form of PSD-95 (PSD-95:S73A). In contrast to young adult mice, in aged animals reward location learning affects only spines that lack PSD-95. The frequency and size of the spines without PSD-95 are increased, while shRNA targeted to PSD-95 affects neither speed of learning nor precision of memory indicating alternative mechanisms to support successful memory formation in old mice. Altogether, our data suggest that dynamic regulation of PSD-95 expression is a mechanism that accelerates learning and improves precision of reward location memory in young mice. The function of PSD-95 in memory processes changes in aged animals.
Brain connectivity measures improve modeling of functional outcome after acute ischemic stroke
Authors: Ktena Sofia Ira , Schirmer Markus D. , Etherton Mark R. , Giese Anne-Katrin , Tuozzo Carissa , Mills Brittany B , Rueckert Daniel , Wu Ona , Rost Natalia S.
Published: March 2019

Background

The ability to model long-term functional outcomes after acute ischemic stroke (AIS) represents a major clinical challenge. One approach to potentially improve prediction modeling involves the analysis of connectomics. The field of connectomics represents the brain’s connectivity as a graph, whose topological properties have helped uncover underlying mechanisms of brain function in health and disease. Specifically, we assessed the impact of stroke lesions on rich club (RC) organization, a high capacity backbone system of brain function.

Methods

In a hospital-based cohort of 41 AIS patients, we investigated the effect of acute infarcts on the brain’s pre-stroke RC backbone and post-stroke functional connectomes with respect to post-stroke outcome. Functional connectomes were created utilizing three anatomical atlases and characteristic path-length (L) was calculated for each connectome. The number of RC regions (NRC) affected were manually determined using each patient’s diffusion weighted image (DWI). We investigated differences inLwith respect to outcome (modified Rankin Scale score (mRS); 90-days; poor: mRS>2) and the National Institutes of Health Stroke Scale (NIHSS; early: 2-5 days; late: 90-day follow-up). Furthermore, we assessed the effect of including NRCandLin ‘outcome’ models, using linear regression and assessing the explained variance (R2).

Results

Of 41 patients (mean age (range): 70 (45-89) years), 61% were male. There were differences inLbetween patients with good and poor outcome (mRS). Including NRC in the backward selection models of outcome, R2increased between 1.3- and 2.6-fold beyond that of traditional markers (age and acute lesion volume) for NIHSS and mRS.

Conclusion

In this proof-of-concept study, we showed that information on network topology can be leveraged to improve modeling of post-stroke functional outcome. Future studies are warranted to validate this approach in larger prospective studies of outcome prediction in stroke.
Single chromosome gains can function as metastasis suppressors and metastasis promoters in colon cancer
Authors: Vasudevan Anand , Baruah Prasamit S. , Smith Joan C. , Wang Zihua , Sayles Nicole M. , Andrews Peter , Kendall Jude , Leu Justin E. , Chunduri Narendra Kumar , Levy Dan , Wigler Michael , Storchová Zuzana , Sheltzer Jason M.
Published: March 2019

Most human tumors display chromosome-scale copy number alterations, and high levels of aneuploidy are frequently associated with advanced disease and poor patient prognosis. To examine the relationship between aneuploidy and cancer progression, we generated and analyzed a series of congenic human cell lines that harbor single extra chromosomes. We find that different aneuploidies can have distinct effects on invasive behavior: across 13 different cell lines, 12 trisomies suppressed invasiveness or were largely neutral, while a single trisomy increased metastatic behavior by triggering a partial epithelial-mesenchymal transition. In contrast, chromosomal instability, which can lead to the development of aneuploidy, uniformly suppressed cellular invasion. By analyzing genomic copy number and survival data from 10,133 cancer patients, we demonstrate that specific aneuploidies are associated with distinct clinical outcomes, and the acquisition of certain aneuploidies is in fact linked with a favorable prognosis. Thus, aneuploidy is not a uniform driver of malignancy, and different chromosome copy number changes can uniquely influence tumor progression. At the same time, the gain of a single chromosome is capable of inducing a profound cell state transition, underscoring how genomic plasticity can engender phenotypic plasticity and lead to the acquisition of enhanced metastatic properties.
White Matter Extension of the Melbourne Children’s Regional Infant Brain Atlas: M-CRIB-WM
Authors: Wen Yao Sarah Hui , Yang Joseph Yuan-Mou , Alexander Bonnie , Wu Michelle Hao , Kelly Claire E. , Ball Gareth , Seal Marc L. , Anderson Peter J. , Doyle Lex W. , Cheong Jeanie L.Y. , Spittle Alicia J. , Thompson Deanne K.
Published: March 2019

Background

Understanding typically developing infant brain structure is crucial in investigating neurological disorders of early childhood. Brain atlases providing standardised identification of neonatal brain regions are key in such investigations. Our previously developed Melbourne Children’s Regional Infant Brain (M-CRIB) and M-CRIB 2.0 neonatal brain atlases provide standardised parcellation of 100 and 94 brain regions respectively, including cortical, subcortical, and cerebellar regions. The aim of this study was to extend the M-CRIB atlas coverage to include 54 white matter regions.

Methods

Participants were ten healthy term-born neonates who comprised the sample for the M-CRIB and M-CRIB 2.0 atlases. WM regions were manually segmented on T2 images and co-registered diffusion tensor imaging-based, direction-encoded colour maps. Our labelled regions are based on those in the JHU-neonate-SS atlas, but differ in the following ways: 1) we included five corpus callosum subdivisions instead of a left / right division; 2) we included a left / right division for the middle cerebellar peduncle; and 3) we excluded the three brainstem divisions. All segmentations were reviewed and approved by a paediatric radiologist and a neurosurgery research fellow for anatomical accuracy.

Results

The resulting neonatal WM atlas comprises 54 WM regions: 24 paired regions, and six unpaired regions comprising five corpus callosum subdivisions and one pontine crossing tract. Detailed protocols for manual WM parcellations are provided, and the M-CRIB-WM atlas is presented together with the existing M-CRIB and M-CRIB 2.0 cortical, subcortical and cerebellar parcellations in ten individual neonatal MRI datasets.

Conclusion

The updated M-CRIB atlas including the WM parcellations will be made publicly available. The atlas will be a valuable tool that will help facilitate neuroimaging research into neonatal WM development in both healthy and diseased states.
Identification of a human adult cardiac stem cell population with neural crest origin
Authors: Höving Anna , Merten Madlen , Schmidt Kazuko Elena , Faust Isabel , Ruiz-Perera Lucia Mercedes , Hachmeister Henning , Sommer Sebastian-Patrick , Fujita Buntaro , Pühler Thomas , Huser Thomas , Greiner Johannes , Kaltschmidt Barbara , Gummert Jan , Knabbe Cornelius , Kaltschmidt Christian
Published: March 2019

Cardiovascular diseases are the major cause of death worldwide, emphasizing the necessity to better understand adult human cardiac cell biology and development. Although the adult heart was considered as a terminally differentiated organ, rare populations of cardiac stem cells (CSCs) have been described so far, with their developmental origin and endogenous function still being a matter of debate.

Here, we identified a Nestin+/S100+/CD105+/Sca1+/cKit-population of CSCs in the myocardium of the adult human heart auricle. Isolated cells showed expression of characteristic neural crest-derived stem cell (NCSC) markers and kept their genetic stability during cultivationin vitro. Cultivated hCSCs efficiently gave rise to functional, beating cardiomyocytes, osteoblasts, adipocytes and neurons. Global transcriptome analysis via RNAseq showed a high similarity between the expression profiles of Nestin+/S100+/CD105+/Sca1+/cKit-hCSCs and adult human NCSCs from the nasal cavity (inferior turbinate stem cells, ITSCs). In detail, 88.1 % of all genes were significantly expressed in both stem cell populations particularly including common NCSC-markers. Based on these observations, we suggest a similar developmental origin of both stem cell populations.

In summary, we identified a human adult cardiac stem cell population with neural crest-origin, which may also contribute to endogenous cardiac tissue homeostasis and tissue repairin vivo.
AMPK-independent LKB1 activity is required for efficient epithelial ovarian cancer metastasis
Authors: Buensuceso Adrian , Valdes Yudith Ramos , DiMattia Gabriel E. , Shepherd Trevor G.
Published: March 2019

Epithelial ovarian cancer (EOC) spreads by direct dissemination of malignant cells and multicellular clusters, known as spheroids, into the peritoneum followed by implantation and growth on abdominal surfaces. Using a spheroid model system of EOC metastasis, we discovered that Liver kinase B1 (LKB1), encoded by theSTK11gene, and its canonical substrate AMP-activated protein kinase (AMPK) are activated in EOC spheroids, yet only LKB1 is required for cell survival. We have now generatedSTK11-knockout cell lines using normal human FT190 cells and three EOC cell lines, OVCAR8, HeyA8, and iOvCa147.STK11KO did not affect growth and viability in adherent culture, but it decreased anchorage-independent growth of EOC cells. EOC spheroids lacking LKB1 had markedly impaired growth and viability, whereas there was no difference in normal FT190 spheroids. To test whether LKB1 loss affects EOC metastasis, we performed intraperitoneal injections of OVCAR8-, HeyA8-, and iOvCa147-STK11KO cells, and respective controls. LKB1 loss exhibited a dramatic reduction on tumour burden and metastatic potential; in particular, OVCAR8-STK11KO tumours had evidence of extensive necrosis, apoptosis and hypoxia. Interestingly, LKB1 loss did not affect AMPKα phosphorylation in EOC spheroids and tumour xenografts, indicating that LKB1 signaling to support EOC cell survival in spheroids and metastatic tumour growth occurs via other downstream mediators. We identified the dual-specificity phosphatase DUSP4 as a commonly upregulated protein due to LKB1 loss; indeed,DUSP4knockdown in HeyA8-STK11KO cells restored spheroid formation and viability. Our results strongly indicate that intact LKB1 activity independent of downstream AMPK signaling is required during EOC metastasis.