bluuebunny/crossref_metadata_2025 huggingface dataset:
Design, Implementation, and Assessment of a Public Comprehensive Specialty Care Program for Early Psychosis
Authors: NORTH CAROL S. , SIMIC ZORICA , BURRUSS JOHN
Published: November 2019

Introduction:

Promising outcomes from early psychosis intervention programs have prompted implementation of early psychosis initiatives nationwide through federal and state funding. The Enhanced Program for Early Psychosis (ePEP) model in north Texas is among the first, if not the first, of these state-funded initiatives to provide detailed reporting of its development and implementation.

Methods:

Restrictive inclusion/exclusion criteria with a 1% eligibility rate resulted in a highly disadvantaged, predominantly minority sample with low educational attainment, prevalent mood disorders and substance misuse, and criminal justice involvement. Program progress was assessed over 1 year through structured diagnostic assessments and measures of psychotic symptoms, depression and anxiety symptoms, psychosocial functioning, and service utilization and costs.

Results:

Implementation challenges included strict income/insurance inclusion and disqualification criteria for program participation, hiring and staff turnover problems, client transportation, and lack of available family to participate in family interventions. Despite these challenges, patients showed reduction in negative psychotic symptoms, hospitalization rates decreased from 29% to 5%, full-time employment improved from 6% to 24%, and probation/parole decreased from 24% to 5%. The mean 1-year per-patient cost was $10,639. Reduced negative symptoms and hospitalizations were associated with service use.

Discussion:

The development and implementation of this pioneering state-funded early psychosis program, based on the National Institute of Mental Health’s Recovery After an Initial Schizophrenia Episode (RAISE) initiative, provide experience and results to inform the implementation of future programs. Its demonstrated success, in spite of many implementation challenges, suggests the potential for future research, including randomized controlled trials to demonstrate substantial benefit and cost-effectiveness of early psychosis programs in real-world settings.
Escalation of Gambling Associated With Aripiprazole: A Case Report and Literature Review
Authors: GIRI YAM R. , PETERU SACHIDANAND R.
Published: November 2019

Impulse-control problems such as gambling, increased spending, hypersexuality, and compulsive eating are thought to be influenced by temperamental, genetic, and physiological risk factors. In addition, dopamine receptor agonists have been implicated in some cases. It is postulated that aripiprazole may cause impulse-control problems because it can produce a hyperdopaminergic state in the mesolimbic pathway (reward system) through its predominant action on dopamine D3 receptors. We present the case of a patient with bipolar disorder and previous gambling behavior, in whom the gambling behavior escalated with the introduction of aripiprazole and its upward titration. The patient’s gambling problems were alleviated with a decrease in aripiprazole dosage. Clinicians should be vigilant for possible gambling and other impulse-control behaviors in patients taking aripiprazole. Our literature review suggests cariprazine and brexpiprazole, which have mechanisms of action similar to that of aripiprazole, may also be associated with possible risks of impulse-control problems and pathologic gambling.
Effectiveness of a 6-Week Day Hospital Treatment for Personality Disorders: Data From a Naturalistic Study
Authors: SAVARD CLAUDIA , CHRÉTIEN MAXIME , GAMACHE DOMINICK , MARANDA JOHANNE , VILLENEUVE EVENS
Published: November 2019

Objective:

To report on the effectiveness of a time-limited day-hospital crisis treatment for personality disorders (PDs) in a naturalistic setting.

Method:

Archival data from 260 patients diagnosed with PDs (202 female, 58 male) who completed a 6-week day-hospital treatment program between 2012 and 2015 were analyzed. Treatment was available upon referral by psychiatrists at local emergency rooms and short-term hospitalization units. Pre-post change was assessed using the Outcome Questionnaire (OQ-45.2).

Results:

Patients significantly improved during treatment on the total OQ-45.2 scale and its 3 subscales. Pre-post changes yielded large effect sizes for the total OQ-45.2 scale and the Symptom Distress subscale, and moderate effect sizes for the Interpersonal Relations and Social Role subscales. Reliable change was observed for 55% of patients for the total scale. Younger patients (18 to 24 y of age) showed larger improvements on social role satisfaction than patients over the age of 30. Overall improvement was larger for patients engaged in social participation at the beginning of treatment.

Conclusions:

This study conducted in a naturalistic setting suggests that a time-limited, 6-week day-hospital treatment program tailored to patients wiith PDs may be effective in reducing overall symptomatology in patients experiencing a crisis episode.
State of the Art Treatment Options for Actual and Potential Sexual Offenders and New Prevention Strategies
Authors: GIBBELS CHARLOTTE , KNEER JONAS , HARTMANN UWE , KRUEGER TILLMANN H.C.
Published: November 2019

Sexual violence is a significant and devastating issue for men and women throughout the world. Its consequences are not only disastrous for victims of sexual violence but are also extremely costly (estimated cost of $41,000 per rape) for society. Successful treatment of sexual offenders is therefore an important goal for society as well as for victims and offenders themselves. Over the years, multiple treatment approaches for sex offenders have been developed. Treatment programs range from the risk-need-responsivity (RNR) model, which focuses on providing tailored treatment for high-risk and low-risk offenders, to psychodynamic models. This article presents an overview for clinicians of state-of-the-art offender treatment, describing the most common treatment approaches, in particular the RNR model, cognitive-behavioral programs (relapse prevention programs, sexual offender treatment programs), psychodynamic approaches (transference-focused psychotherapy, mentalization-based therapy), the Good Lives Model, as well as pharmacological options. In addition, it provides an evaluation of the various treatment programs. However, given the fact that most acts of sexual violence will never be reported to the police, the question arises if treating convicted perpetrators is enough. Do we need rather—in terms of preventive work—a program for potential sexual offenders and men with delinquent sexual fantasies? Given the prevalence of sexual violence and its impact on victims, society, and the medical community, it would be remiss not to try to reach potential/unconvicted perpetrators. This article offers novel ideas and a project the goal of which is to prevent sexual offenses against women by introducing the “I CAN CHANGE” program from Hannover Medical School.
L-Methylfolate Calcium Supplementation in Adolescents and Children: A Retrospective Analysis
Authors: RAINKA MICHELLE , ALADEEN TRACI , WESTPHAL ERICA , MEANEY JACQUELINE , GENGO FRAN , GREGER JESSICA , CAPOTE HORACIO
Published: November 2019

Previous studies have shown l-methylfolate to be a safe and beneficial therapy for neuropsychiatric conditions, including major depressive disorder and schizophrenia in adults. The purpose of this study was to assess safety and describe patient experience using l-methylfolate calcium in a real-world pediatric and adolescent population. A retrospective chart review of patients (7 to 20 y of age, mean age 16 y) prescribed l-methylfolate calcium at a psychiatry clinic in Amherst, NY, between January 1, 2010 and November 10, 2015 was conducted. Patients to whom l-methylfolate calcium 15 mg/d (n=139) or 7.5 mg/d (n=7) was administered were identified; 44 patients who were prescribed but to whom l-methylfolate calcium was not administered were included as a comparator population. Common neuropsychiatric diagnoses included anxiety disorders (68% in the treatment population vs. 50% in the comparator population) and mood disorders (57% in the treatment population vs. 52% in the comparator population). Antidepressants (69% vs. 55%) and mood stabilizers or antiepileptic drugs (63% vs. 57%) were frequently prescribed in combination with l-methylfolate calcium. Adverse events occurred less frequently in the treated population, possibly due to the addition of l-methylfolate calcium (10% vs. 25%, P=0.02). The most common adverse events in the treated population were impaired sleep (5 patients) and increased anxiety (3 patients). Rates of laboratory abnormalities did not differ significantly between the treated and comparator populations (P=0.13). Positive subjective treatment experiences were reported by 22.5% of treated patients and negative subjective treatment experiences were reported by 5.4% of treated patients. L-methylfolate calcium was well-tolerated in a pediatric/adolescent population and may provide benefits for patients with a range of neuropsychiatric conditions.
Hallucinogens and Their Therapeutic Use: A Literature Review
Authors: BEGOLA MATTHEW J. , SCHILLERSTROM JASON E.
Published: November 2019

The exploration of possible therapeutic benefits of hallucinogenic substances has undergone a revitalization in the past decade. This literature review investigated the published literature regarding the psychotherapeutic uses of hallucinogens in psychiatric disorders. The results showed that a variety of substances have been evaluated in the treatment of psychiatric disorders, including ayahuasca, ibogaine, ketamine, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine, and psilocybin. The conditions treated ranged from depression to autism, with the largest volume of research dedicated to substance use disorders. The majority of studies that were reviewed demonstrated significant associations with improvement in the conditions investigated. However, it was difficult to draw definitive conclusions as most studies suffered from small sample sizes, inconsistent measures, and poor study design. To properly assess the risks and potential benefits of hallucinogens in psychiatric treatment, there is a need for well designed, standardized studies that demonstrate the impact of hallucinogenic substances on psychiatric conditions.
Pediatric Nonsuicidal Self-Injury: A Call to Action for Inpatient Staff Training
Authors: PLUHAR EMILY , FREIZINGER MELISSA B. , NIKOLOV ROUMEN N. , BURTON E. THOMASEO
Published: November 2019

The rising prevalence of nonsuicidal self-injury (NSSI) in pediatric populations along with the recent inclusion of NSSI as a condition for further study in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) have increased the focus on the assessment and treatment of NSSI among youth. Despite the frequent occurrence of NSSI in inpatient psychiatric treatment settings, there are no empirically based assessment protocols to guide clinical staff. This article presents findings from a needs assessment conducted with staff at a state-run child and adolescent inpatient treatment facility. The purpose was to assess the need for formalized NSSI training among staff. A questionnaire was developed to evaluate whether staff had received formal training in NSSI assessment and treatment as well as typical practice responses to patients engaging in NSSI behaviors. The questionnaire also evaluated staff comfort and confidence in their knowledge and skills concerning the assessment and treatment of NSSI among children and adolescents. Respondents were 126 clinical staff, most of whom were nursing staff. Only a minority of staff reported having received formal NSSI training, and a third of respondents indicated that they do not typically assess for NSSI at all. Although a substantial percentage of clinical staff self-reported comfort and confidence with assessing and treating NSSI, fewer than 10% demonstrated accurate skill. Formal training in NSSI is associated with positive outcomes for both patients and staff in general healthcare settings. These findings suggest that similar training for staff on pediatric inpatient psychiatric units will likely foster comfort, confidence, and accuracy, thereby improving outcomes for children and adolescents engaging in NSSI behaviors.
Clinical Experience in Emergency Management of Severe Facial Trauma
Authors: Gao Hai , Wang Wangshu , Geng Yujia , Shao Ying
Published: November 2019

Background:

Published reports describing management of complex facial lacerations in the emergency department are limited, and there is little guidance on the treatment of massive soft tissue avulsions of the head and face or severely contaminated head and face lacerations. Here, the authors report on the wealth of clinical experience they have gained in treating major head and facial injuries through an emergency trauma repair platform that was established in the department of orthopedic surgery at their hospital.

Methods:

Six patients with massive soft tissue avulsions of the head and face caused by trauma were treated in our department between September 2017 and December 2018. Avulsion injuries occurred to the eyelids, ears, face, and part of the scalp. Defects extended from the skin to the surface of the bone. Emergency surgical repair involved reasonable debridement of the wound surface, accurate and meticulous suture, and use of local skin flaps.

Results:

No patients experienced postoperative complications, such as necrosis, infection, or scar hyperplasia. Our postoperative satisfaction survey showed that 3 patients were very satisfied and 1 patient was relatively satisfied with their outcomes. Several patients (2/6) still had some degree of deformity in the soft tissue around the eyes, which required further surgery

Conclusion:

Satisfactory functional and aesthetic outcomes can be achieved through reasonable debridement of the wound surface, accurate and meticulous suture, and use of local skin flaps in patients with massive soft tissue avulsions of the head and face caused by trauma.
Prevalence and mechanisms of fluoroquinolone-resistant Escherichia coli among sheltered companion animals
Authors: Umeda Kaoru , Hase Atsushi , Fukuda Akira , Matsuo Masashi , Horimoto Tomoaki , Ogasawara Jun
Published: November 2019

To better understand the prevalence of fluoroquinolone-resistant

Escherichia coli

among sheltered companion animals, we conducted a screening study of 38 dogs and 78 cats and investigated the resistance mechanisms and characteristics of the isolates. Fluoroquinolone-resistant

E. coli

was detected in 18 dogs (47.4 %) and 14 cats (17.9 %). The isolates carried one to four mutations in the gyrA, parC and parE genes of the quinolone resistance-determining region, and the number of mutations was proportional to the MIC for ciprofloxacin. For plasmid-mediated quinolone resistance, aac-(6′)-Ib-cr was detected in nine isolates, qnrS in five isolates and qnrB in one isolate. A relationship between the presence of these genes and MIC for ciprofloxacin was not apparent. Statistical analysis indicated that fluoroquinolone-resistant

E. coli

was widely distributed among sheltered companion animals with various attributes. This may relate to the wide dissemination of fluoroquinolone resistance among humans and other animals in Japan.
Fatigue, effort perception and central activation failure in chronic stroke survivors: a TMS and fMRI investigation
Authors: Turner Isobel F , Ward Nick S , Kuppuswamy Annapoorna
Published: November 2019

Fatigue is commonly seen in stroke survivors and the most common manifestation of fatigue is the requirement of high effort for activities of daily life. In this study we set out to identify the neural correlates of perceived effort and central activation failure, a neurophysiological measure correlated with perceived effort. Methods: Twelve chronic stroke survivors participated in this study. Fatigue levels were quantified using the Fatigue Severity Scale -7, perceived effort was quantified using a 1-10 numerical rating scale while performing an isometric biceps hold task, Central Activation Failure was quantified using the modified twitch interpolation technique using Transcranial Magnetic Stimulation and functional Magnetic Resonance Imaging was used to measure blood-oxygen-level dependent signal (BOLD) from the brain while the participant performed a hand grip task. Analysis: Following standard pre-processing procedures for fMRI data using SPM software, co-variance of BOLD signal with perceived effort levels and central activation failure was evaluated. Correlation analysis was performed between measures of fatigue and effort. Results: The main findings of this study were 1) high fatigue was associated with high perceived effort 2) higher perceived effort was associated with greater increase in BOLD fMRI activity in pre-SMA and the ipsilateral inferior frontal gyrus with increasing force 3) greater Central Activation Failure was associated with higher increase in BOLD fMRI activity in bilateral caudate, contralateral superior frontal gyrus and pre-motor cortices with increasing force.
CDK13 Mutations Drive Melanoma via Accumulation of Prematurely Terminated Transcripts
Authors: Insco Megan L. , Abraham Brian J. , Dubbury Sara J. , Dust Sofia , Wu Constance , Chen Kevin Y. , Liu David , Ludwig Calvin G. , Bellaousov Stanislav , Fabo Tania , Henriques Telmo , Adelman Karen , Geyer Matthias , Sharp Phillip A. , Young Richard A. , Boutz Paul L. , Zon Leonard I.
Published: November 2019

Transcriptional Cyclin Dependent Kinases modulate RNA Polymerase II function to impact gene expression. Here, we show that CDK13 is mutated in 4% of patient melanomas and mutation or downregulation is associated with poor overall survival. Mutant CDK13 lacks kinase activity and overexpression in zebrafish leads to accelerated melanoma. CDK13 mutant fish and human melanomas accumulate prematurely terminated RNAs that are translated into truncated proteins. CDK13 binds to and regulates the phosphorylation of ZC3H14, a member of the PolyA eXosome Targeting (PAXT) RNA degradation complex. ZC3H14 phosphorylation recruits the PAXT complex to degrade prematurely terminated polyadenylated transcripts in the nucleus. In the presence of mutant CDK13, ZC3H14 phosphorylation is compromised and consequently fails to recruit the PAXT complex, leading to truncated transcript stabilization. This work establishes a role for CDK13 and the PAXT nuclear RNA degradation complex in cancer and has prognostic significance for melanoma patients with mutated or downregulated CDK13.
iTRAQ-based proteomic and phosphoproteomic analyses of STRIPAK mutants from the fungusSordaria macrosporaidentifies a conserved serine phosphorylation site in PAK kinase CLA4 to be important for sexual development and polarized growth
Authors: Märker R , Blank-Landeshammer B , Beier-Rosberger A , Sickmann A , Kück U
Published: November 2019

The highly conserved striatin-interacting phosphatases and kinases (STRIPAK) complex regulates phosphorylation of developmental proteins in eukaryotic microorganisms, animals, and humans. To first identify potential targets of STRIPAK, we performed extensive isobaric tags for relative and absolute quantification (iTRAQ)-based proteomic and phosphoproteomic analyses in the filamentous fungusSordaria macrospora.In total, we identified 4,193 proteins and 2,489 phosphoproteins, which are represented by 10,635 phosphopeptides. By comparing phosphorylation data from wild-type and mutants, we identified 228 phosphoproteins to be regulated in all three STRIPAK mutants, thus representing potential targets of STRIPAK. To provide an exemplarily functional analysis of a STRIPAK-dependent phosphorylated protein, we selected CLA4, a member of the conserved p21-activated kinase (PAK) family. Functional characterization of the Δcla4 deletion strain showed that CLA4 controls sexual development and polarized growth. To determine the functional relevance of CLA4 phosphorylation and the impact of specific phosphorylation sites on development, we next generated phospho-mimetic and -deficient variants of CLA4. This analysis identified (de)phosphorylation of a highly conserved serine (S685) residue in the catalytic domain of CLA4 as being important for fungal cellular development. Collectively, these analyses significantly contribute to the understanding of the mechanistic function of STRIPAK as a phosphatase and kinase signaling complex.
Formal string instrument training in a class setting enhances cognitive and sensorimotor development of primary school children
Authors: James Clara E. , Zuber Sascha , Dupuis-Lozeron Elise , Abdili Laura , Gervaise Diane , Kliegel Matthias
Published: November 2019

This randomized controlled trial shows for the first time that focused musical instrumental practice as compared to traditional sensitization to music provokes robust cognitive and sensorimotor transfer effects. Over the last two years of primary school (10-12-year-old children), sixty-nine children received biweekly musical instruction by professional musicians within the regular school curriculum. The intervention group learned to play string instruments, whereas the control group, peers in parallel classes, was sensitized to music via listening, theory, and some practice. Broad benefits manifested in the intervention group as compared to the control group for working memory, attention, processing speed, cognitive flexibility, matrix reasoning, sensorimotor hand function and bimanual coordination Apparently, learning to play a complex instrument in a dynamic group setting impacts development much stronger than classical sensitization to music. Our results therefore highlight the added value of intensive musical instrumental training in a group setting, encouraging general implementation in public primary schools, better preparing children for secondary school and for daily living activities.

Highlights

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Music practice produces multiple cognitive transfer effects in school children

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Making music causes stronger cognitive benefits than sensitization to music

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Music practice in a class setting improves executive functions and abstract thinking

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Playing string instruments enhances fine manual dexterity and bimanual coordination
The resolution revolution in cryoEM requires new sample preparation procedures: A rapid pipeline to high resolution maps of yeast FAS
Authors: Joppe Mirko , D’Imprima Edoardo , Salustros Nina , Paithankar Karthik S. , Vonck Janet , Grininger Martin , Kühlbrandt Werner
Published: November 2019

Single-particle electron cryo-microscopy (cryoEM) has undergone a “resolution revolution” that makes it possible to characterize megadalton (MDa) complexes at atomic resolution without crystals. To fully exploit the new opportunities in molecular microscopy, new procedures for the cloning, expression and purification of macromolecular complexes need to be explored. Macromolecular assemblies are often unstable, and invasive construct design or inadequate purification conditions or sample preparation methods can result in disassembly or denaturation. The structure of the 2.6 MDa yeast fatty acid synthase (FAS) has been studied by electron microscopy since the 1960s. We report a new, streamlined protocol for the rapid production of purified yeast FAS for structure determination by high-resolution cryoEM. Together with a companion protocol for preparing cryoEM specimens on a hydrophilized graphene layer, our new protocol has yielded a 3.1 Å map of yeast FAS from 15,000 automatically picked particles within a day. The high map quality enabled us to build a complete atomic model of an intact fungal FAS.
DeepDBP: Deep Neural Networks for Identification of DNA-binding Proteins
Authors: Shadab Shadman , Khan Md Tawab Alam , Neezi Nazia Afrin , Adilina Sheikh , Shatabda Swakkhar
Published: November 2019

DNA-Binding proteins (DBP) are associated with many cellular level functions which includes but not limited to body’s defense mechanism and oxygen transportation. They bind DNAs and interact with them. In the past DBPs were identified using experimental lab based methods. However, in the recent years researchers are using supervised learning to identify DBPs solely from protein sequences. In this paper, we apply deep learning methods to identify DBPs. We have proposed two different deep learning based methods for identifying DBPs: DeepDBP-ANN and DeepDBP-CNN. DeepDBP-ANN uses a generated set of features trained on traditional neural network and DeepDBP-CNN uses a pre-learned embedding and Convolutional Neural Network. Both of our proposed methods were able to produce state-of-the-art results when tested on standard benchmark datasets.DeepDBP-ANN had a train accuracy of 99.02% and test accuracy of 82.80%.And DeepDBP-CNN though had train accuracy of 94.32%, it excelled at identifying test instances with 84.31% accuracy. All methods are available codes and methods are available for use at: https://github.com/antorkhan/DNABinding.
The olfactory bulb contributes to the adaptation of odor responses: the input-output transformation
Authors: Storace Douglas A. , Cohen Lawrence B.
Published: November 2019

While humans and other animals exhibit adaptation to odorants, the neural mechanisms involved in this process are incompletely understood. One possibility is that it primarily occurs as a result of the interactions between odorants and odorant receptors expressed on the olfactory sensory neurons in the olfactory epithelium. In this scenario, adaptation would arise as a peripheral phenomenon transmitted into the brain. An alternative possibility is that adaptation occurs as a result of processing in the brain. Here we asked whether the olfactory bulb, the first stage of olfactory information processing in the brain, is involved in perceptual adaptation. Multicolor imaging was used to simultaneously measure the olfactory receptor nerve terminals (input) and mitral/tufted cell apical dendrites (output) that innervate the olfactory bulb glomerular layer. Repeated odor stimulation of the same concentration resulted in a decline in the output maps, while the input remained relatively stable. The results indicate that the mammalian olfactory bulb participates in olfactory adaptation.
Multiple chromosomal inversions contribute to adaptive divergence of a dune sunflower ecotype
Authors: Huang Kaichi , Andrew Rose L. , Owens Gregory L. , Ostevik Kate L. , Rieseberg Loren H.
Published: November 2019

Both models and case studies suggest that chromosomal inversions can facilitate adaptation and speciation in the presence of gene flow by suppressing recombination between locally adapted alleles. Until recently, however, it has been laborious and time-consuming to identify and genotype inversions in natural populations. Here we apply RAD sequencing data and newly developed population genomic approaches to identify putative inversions that differentiate a sand dune ecotype of the prairie sunflower (Helianthus petiolaris) from populations found on the adjacent sand sheet. We detected seven large genomic regions that exhibit a different population structure than the rest of the genome and that vary in frequency between dune and non-dune populations. These regions also show high linkage disequilibrium and high heterozygosity between, but not within haplotypes, consistent with the behavior of large inversions, an inference subsequently validated in part by comparative genetic mapping. Genome-environment association analyses show that key environmental variables, including vegetation cover and soil nitrogen, are significantly associated with inversions. The inversions co-locate with previously described “islands of differentiation,” and appear to play an important role in adaptive divergence and incipient speciation withinH. petiolaris.
Patient stratification of clear cell renal cell carcinoma using the global transcription factor activity landscape derived from RNA-seq data
Authors: Zhu Yanyan , Cang Shundong , Chen Bowang , Gu Yue , Jiang Miaomiao , Yan Junya , Shao Fengmin , Huang Xiaoyun
Published: November 2019

Clear cell renal cell carcinoma represents the most common type of kidney cancer. Precision medicine approach to ccRCC requires an accurate stratification of patients that can predict prognosis and guide therapeutic decision. Transcription factors are implicated in the initiation and progression of human carcinogenesis. However, no comprehensive analysis of transcription factor activity has been proposed so far to realize patient stratification. Here we propose a novel approach to determine the subtypes of ccRCC patients based on global transcription factor activity landscape. Using the TCGA cohort dataset, we identified different subtypes that have distinct upregulated biomarkers and altered biological pathways. More important, this subtype information can be used to predict the overall survival of ccRCC patients. Our results suggest that transcription factor activity can be harnessed to perform patient stratification.
Biosynthetic engineering of the antifungal, anti-MRSA auroramycin
Authors: Yeo Wan Lin , Heng Elena , Tan Lee Ling , Lim Yi Wee , Ching Kuan Chieh , Tsai De-Juin , Jhang Yi Wun , Lauderdale Tsai-Ling , Shia Kak-Shan , Zhao Huimin , Ang Ee Lui , Zhang Mingzi M. , Lim Yee Hwee , Wong Fong T.
Published: November 2019

Using an established CRISPR-Cas mediated genome editing technique for streptomycetes, we explored the combinatorial biosynthesis potential of the auroramycin biosynthetic gene cluster in Streptomyces roseoporous. Auroramycin is a potent anti-MRSA polyene macrolactam. In addition, it also displays antifungal activities, which is unique among structurally similar polyene macrolactams, such as incednine and silvalactam. In this work, we employed different engineering strategies to target glycosylation and acylation biosynthetic machineries within its recently elucidated biosynthetic pathway. Six auroramycin analogs with variations in C-, N-methylation, hydroxylation and extender units incorporation were produced and characterized. By comparing the bioactivity profiles of these analogs, we determined that unique disaccharide motif of auroramycin is essential for its antimicrobial bioactivity. We further demonstrated that C-methylation of the 3, 5-epi-lemonose unit, which is unique among structurally similar polyene macrolactams, is key to its antifungal activity.
Redefining Interleukin 11 as a regeneration-limiting hepatotoxin
Authors: Widjaja Anissa A. , Dong Jinrui , Adami Eleonora , Viswanathan Sivakumar , Ng Benjamin , Singh Brijesh K. , Lim Wei Wen , Zhou Jin , Pakkiri Leroy S. , Shekeran Shamini G. , Tan Jessie , Lim Sze Yun , Wang Mao , Holgate Robert , Hearn Arron , Yen Paul M. , Chothani Sonia P. , Felkin Leanne E. , Dear James W. , Drum Chester L. , Schafer Sebastian , Cook Stuart A.
Published: November 2019

Acetaminophen (APAP) overdose is a leading cause of untreatable liver failure. In the mouse model of APAP-induced liver injury (AILI), the administration of recombinant human interleukin 11 (rhIL11) is protective. Here we show that the beneficial effect of rhIL11 in the mouse is due to its unexpected and paradoxical inhibition of endogenous mouse IL11 activity. Contrary to the accepted paradigm IL11 is a potent hepatotoxin across species, which is secreted from damaged hepatocytes to drive an autocrine loop of NOX4 and JNK-dependent apoptosis. Mice with hepatocyte-specific Il11 expression spontaneously develop liver failure whereas those with Il11ra1 deletion are remarkably protected from AILI. Neutralizing anti-IL11R antibodies administered to moribund mice 10 hours following a lethal APAP overdose results in 90% survival that is associated with very large liver regeneration. Our data overturn a misconception, identify a new disease mechanism and suggest IL11 as a therapeutic target for liver regeneration.
The Mammalian Cytosolic Thioredoxin Reductase Pathway Acts via a Membrane Protein to Reduce ER-localised Proteins
Authors: Cao Xiaofei , Lilla Sergio , Cao Zhenbo , Pringle Marie Anne , Oka Ojore BV , Robinson Philip J , Szmaja Tomasz , van Lith Marcel , Zanivan Sara , Bulleid Neil J
Published: November 2019

Folding of proteins entering the mammalian secretory pathway requires the insertion of the correct disulfide bonds. Disulfide formation involves both an oxidative pathway for their insertion and a reductive pathway to remove incorrectly formed disulfides. Reduction of these disulfides is critical for correct folding and degradation of misfolded proteins. Previously, we showed that the reductive pathway is driven by NADPH generated in the cytosol. Here, by reconstituting the pathway using purified proteins and ER microsomal membranes, we demonstrate that the thioredoxin reductase system provides the minimal cytosolic components required for reducing proteins within the ER lumen. In particular, saturation of the pathway and its protease sensitivity demonstrates the requirement for a membrane protein to shuttle electrons from the cytosol to the ER lumen. These results provide compelling evidence for the critical role of the cytosol in regulating ER redox homeostasis to ensure correct protein folding and to facilitate the degradation of misfolded ER proteins.
Frontoparietal action-oriented codes support novel instruction implementation
Authors: González-García Carlos , Formica Silvia , Wisniewski David , Brass Marcel
Published: November 2019

A key aspect of human cognitive flexibility concerns the ability to convert complex symbolic instructions into novel behaviors. Previous research proposes that this transformation is supported by two neurocognitive states: an initial declarative maintenance of task knowledge, and an implementation state necessary for optimal task execution. Furthermore, current models predict a crucial role of frontal and parietal brain regions in this process. However, whether declarative and procedural signals independently contribute to implementation remains unknown. We report the results of an fMRI experiment in which participants executed novel instructed stimulus-response associations. We then used a pattern-tracking procedure to quantify the contribution of format-unique signals during instruction implementation. This revealed independent procedural and declarative representations of novel S-Rs in frontoparietal areas, prior to execution. Critically, the degree of procedural activation predicted subsequent behavioral performance. Altogether, our results suggest an important contribution of frontoparietal regions to the neural architecture that regulates cognitive flexibility.
Molecular Screening of Hemoglobin S Variant in Anemia Patients of Eastern UP Population
Authors: Rai Vandana , Yadav Upendra , Kumar Pradeep
Published: November 2019

Hemoglobinopathies are the most common type of inherited disease in human. in India the most frequent and clinically significant hemoglobin structural variants are HbS, HbD and HbE. The HbS mutation, in which a glutamic acid at position 6 in the β chain is substituted for valine Sickle cell disease is a major health problem in some parts of India. 2 ml blood sample was collected from 350 anemia patient and PCR-RFLP method was used for hemoglobin S analysis. Out of 350 samples, in four individuals, HbS mutation was found in homozygous (β 6/β 6) condition. All four individuals are Sickle cell cases. In conclusion, the percentage of Sickle cell disease was observed as 1.14% in Eastern UP anemic patients.
ProSPr: Democratized Implementation of Alphafold Protein Distance Prediction Network
Authors: Billings Wendy M , Hedelius Bryce , Millecam Todd , Wingate David , Corte Dennis Della
Published: November 2019

Deep neural networks have recently enabled spectacular progress in predicting protein structures, as demonstrated by DeepMin’s winning entry with Alphalfold at the latest Critical Assessment, of Structure Prediction competition (CASP13). The best protein prediction pipeline leverages intermolecular distance predictions to assemble a final protein model, but this distance prediction network has not been published. Here, we make a trained implementation of this network available to the broader scientific community. We also benchmark its predictive power in the related task of contact prediction against the CASP13 contact prediction winner TripletRes. Access to ProSPr will enable other labs to build on best in class protein distance predictions and to engineer superior protein reconstruction methods.
Mul1 suppresses Nlrp3 inflammasome activation through ubiquitination and degradation of Asc
Authors: Kim June-Hyung , Lee Yunjong , Suh Gee Young , Lee Yun-Song
Published: November 2019

Activation of the Nlrp3 inflammasome consisting of three major components, Nlrp3, Asc, and pro-caspase-1, results in the activation of caspase-1 and subsequent proteolytic cleavage of pro-IL-1β and pro-IL-18. To avoid excessive inflammatory response, the Nlrp3 inflammasome has to be precisely controlled. In this study, we show that the mouse mitochondrial E3 ubiquitin protein ligase (Mul1) suppresses Nlrp3 inflammasome activation through ubiquitination and degradation of Asc. In J774A.1 cells, Mul1 overexpression attenuated Nlrp3 activation, whereas Mul1 knockdown augmented Nlrp3 activation in terms of IL-1β secretion and cleavage of pro-caspase-1 and pro-IL-1β. Mul1 interacted with Asc, and ubiquitinated it at K21, K22, K26, and K55 residues, in a K48-linked manner, leading to proteasomal degradation. Convincingly, Mul1-mediated suppression of Nlrp3 activation was inhibited by K21R-, K22R-, K26R-, K52R-Asc mutants in RAW264.7 cells, when compared with the wild-type Asc. Furthermore, Aim2 inflammasome activation was also inhibited by Mul1 in the wild-type Asc-, but not in mutant Asc-expressing RAW264.7 cells. Taken together, these data suggest that Mul1 suppresses Nlrp3 inflammasome activation, through Asc ubiquitination and degradation.
Genetic interaction between two unlinked loci underlies the loss of self-incompatibility inArabidopsis lyrata
Authors: Li Yan , van Kleunen Mark , Stift Marc
Published: November 2019

As the first step towards the evolution of selfing from obligate outcrossing, identifying the key mutations underlying the loss of self-incompatibility is of particular interest. However, our current knowledge is primarily based on sequence-based comparisons between selfing species and their self-incompatible relatives, which makes it hard to distinguish causal from secondary mutations. To by-pass this problem, we inferred the genetic basis of the loss of self-incompatibility by intercrossing plants from twelve geographically interspersed outcrossing and selfing populations of North-AmericanArabidopsis lyrataand determining the breeding system of 1,580 progeny. Self-incompatibility was not restored after crosses between different self-compatible populations. Equal frequencies of self-compatible and self-incompatible progeny emerged from crosses between parents with different breeding systems. We propose a two-locus genetic model for the loss of self-incompatibility in which specificS-locus haplotypes (S1andS19) are associated with loss of self-incompatibility through their interaction with an unlinked modifier.
A hidden integral structure endows Absolute Concentration Robust systems with resilience to dynamical concentration disturbances
Authors: Cappelletti Daniele , Gupta Ankit , Khammash Mustafa
Published: November 2019

Biochemical systems that express certain chemical species of interest at the same level at any positive equilibrium are called “absolute concentration robust” (ACR). These species behave in a stable, predictable way, in the sense that their expression is robust with respect to sudden changes in the species concentration, regardless the new positive equilibrium reached by the system. Such a property has been proven to be fundamentally important in certain gene regulatory networks and signaling systems. In the present paper, we mathematically prove that a well-known class of ACR systems studied by Shinar and Feinberg in 2010 hides an internal integral structure. This structure confers these systems with a higher degree of robustness that what was previously unknown. In particular, disturbances much more general than sudden changes in the species concentrations can be rejected, and robust perfect adaptation is achieved. Significantly, we show that these properties are maintained when the system is interconnected with other chemical reaction networks. This key feature enables design of insulator devices that are able to buffer the loading effect from downstream systems - a crucial requirement for modular circuit design in synthetic biology.
Alpha-synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson’s disease
Authors: Cole Tracy A. , Zhao Hien , Collier Timothy J. , Sandoval Ivette , Sortwell Caryl E. , Steece-Collier Kathy , Daley Brian F. , Booms Alix , Lipton Jack , Welch Mackenzie , Berman Melissa , Jandreski Luke , Graham Danielle , Weihofen Andreas , Celano Stephanie , Schulz Emily , Cole-Strauss Allyson , Luna Esteban , Quach Duc , Mohan Apoorva , Bennett C. Frank , Swayze Eric E. , Kordasiewicz Holly B. , Luk Kelvin C. , Paumier Katrina L.
Published: November 2019

Parkinson’s disease (PD) is a prevalent neurodegenerative disease with no approved disease-modifying therapies. Multiplications, mutations, and single nucleotide polymorphisms in the SNCA gene, encoding alpha-synuclein protein (aSyn), either cause or increase risk for PD. Intracellular accumulations of aSyn are pathological hallmarks of PD. Taken together, reduction of aSyn production may provide a disease-modifying therapy for PD. We show that antisense oligonucleotides (ASOs) reduce production of aSyn in rodent pre-formed fibril (PFF) models of PD. Reduced aSyn production leads to prevention and removal of established aSyn pathology and prevents dopaminergic cell dysfunction. In addition, we address the translational potential of the approach through characterization of human SNCA targeting ASOs that efficiently suppress the human SNCA transcript in vivo. We demonstrate broad activity and distribution of the human SNCA ASOs throughout the non-human primate brain and a corresponding decrease in aSyn cerebral spinal fluid (CSF) levels. Taken together, these data suggest that by inhibiting production of aSyn it may be possible to reverse established pathology and thus supports the development of SNCA ASOs as a potentially disease modifying therapy for PD and related synucleinopathies.

Antisense oligonucleotides designed against SNCA, which are progressing to the clinic, have the potential to be a disease modifying therapeutic for Parkinson’s disease patients.
Microfluidic Chip for Label-Free Removal of Teratoma-forming Cells from Therapeutic Human Stem Cells
Authors: Wellmerling Kyle , Lehmann Christian , Singh Ankur , Kirby Brian
Published: November 2019

Teratoma formation remains a safety concern in therapeutic cells derived from human-induced pluripotent stem cells (hiPSCs). Residual Teratoma forming cells are present in small numbers in differentiated hiPSC cultures and yet are of significant roadblock to the manufacturing and clinical translation of stem cell therapies. Rare cells are often difficult to remove with standard flow cytometry or magnetic bead sorting techniques. Here, we first characterized time-dependent expression of a teratoma marker, stage-specific embryonic antigen (SSEA)-5, which binds the H type-1 glycan during neural differentiation of hiPSCs. We engineered a microfluidic geometrically enhanced differential immunocapture (GEDI) technology to remove SSEA-5+ rare cells from hiPSC-derived neural progenitor cells (hiPSC-NPCs). The GEDI chip presents a facile tool to potentially functionalize with multiple antibodies and robustly enhance hiPSC-derived cell population safety prior to therapeutic transplantation. The approach is potentially amenable to generate a wide variety of high-quality therapeutic cells and can be integrated within the pipeline of cell manufacturing to improve patient safety and reduce the cost of manufacturing through early removal of undesirable cell types.
Functional connectivity between the cerebellum and somatosensory areas implements the attenuation of self-generated touch
Authors: Kilteni Konstantina , Ehrsson H. Henrik
Published: November 2019

Since the early 1970s, numerous behavioral studies have shown that self-generated touch feels less intense than the same touch applied externally. Computational motor control theories have suggested that cerebellar internal models predict the somatosensory consequences of our movements and that these predictions attenuate the perception of the actual touch. Despite this influential theoretical framework, little is known about the neural basis of this predictive attenuation. This is due to the limited number of neuroimaging studies, the presence of conflicting results about the role and the location of cerebellar activity, and the lack of behavioral measures accompanying the neural findings. Here, we combined psychophysics with functional magnetic resonance imaging to detect the neural processes underlying somatosensory attenuation in male and female healthy human participants. Activity in bilateral secondary somatosensory areas was attenuated when the touch was presented during a self-generated movement (self-generated touch) than in the absence of movement (external touch). An additional attenuation effect was observed in the cerebellum that is ipsilateral to the passive limb receiving the touch. Importantly, we further found that the degree of functional connectivity between the ipsilateral cerebellum and the contralateral primary and bilateral secondary somatosensory areas was linearly and positively related to the degree of behaviorally assessed attenuation; that is, the more participants perceptually attenuated their self-generated touches, the stronger this corticocerebellar coupling. Collectively, these results suggest that the ipsilateral cerebellum is fundamental in predicting self-generated touch and that this structure implements somatosensory attenuation via its functional connectivity with somatosensory areas.

Significance statement

When we touch our hand with the other, the resulting sensation feels less intense than when another person or a machine touches our hand with the same intensity. Early computational motor control theories have proposed that the cerebellum predicts and cancels the sensory consequences of our movements; however, the neural correlates of this cancelation remain unknown. By means of functional magnetic resonance imaging, we show that the more participants attenuate the perception of their self-generated touch, the stronger the functional connectivity between the cerebellum and the somatosensory cortical areas. This provides conclusive evidence about the role of the cerebellum in predicting the sensory feedback of our movements and in attenuating the associated percepts via its connections to early somatosensory areas.