bluuebunny/crossref_metadata_2025_split huggingface dataset:
Examining side effect variation in antipsychotic treatment and schizophrenia spectrum disorders
Authors: Neumeier Maria S. , Homan Stephanie , Vetter Stefan , Seifritz Erich , Kane John M. , Huhn Maximilian , Leucht Stefan , Homan Philipp 
Published: July 2020

BackgroundSide effects of antipsychotic drugs play a key role in non-adherence and discontinuation of treatment in schizophrenia spectrum disorders (SSD). Precision medicine aims to minimize such side effects by selecting the right treatment for the right patient. However, to determine the extent of precision medicine that is required, we need to (1) show that there is indeed variation in side effects and (2) estimate the amount of variation in those side effects between patients. While clinical impression suggests that such variation is considerable, analyzing how side effect variation differs between treatment and control can address this question more formally. Here, we hypothesized to find larger side effect variation in treatment compared with control in patients treated with second generation antipsychotics.MethodsWe included double-blind, placebo-controlled, randomized controlled trials of adults with a diagnosis of SSD and prescription for licensed antipsychotic drugs. Standard deviations of the pre-post treatment differences of weight gain, prolactin levels, and corrected QT (QTc) times were extracted. Data quality and validity were ensured by following the PRISMA guidelines. The outcome measure was the overall variability ratio of treatment to control across randomized controlled trials (RCTs). Individual variability ratios were weighted by the inverse-variance method and entered into a random-effects model.ResultsWe included N = 16578 patients for weight gain, N = 16633 patients for prolactin levels, and N = 10384 patients for QTc time. Variability ratios (VR) were significantly increased for weight gain (VR = 1.08; 95% CI: 1.02 - 1.14; P = 0.004) and prolactin levels (VR = 1.38; 95% CI: 1.17 - 1.62; P < 0.001) but did not reach significance for QTc time (VR = 1.05; 95% CI: 0.98 - 1.12; P = 0.135).ConclusionWe found increased variability in major side effects in patients with SSD under treatment with second generation antipsychotics, suggesting that subgroups of patients or even individual patients may benefit from improved treatment allocation through stratified or personalized medicine, respectively.
A multi-phenotype genome-wide association study of clades causing tuberculosis in a Ghanaian- and South African cohort
Authors: Müller Stephanie J. , Schurz Haiko , Tromp Gerard , van der Spuy Gian D. , Hoal Eileen G. , van Helden Paul D. , Owusu-Dabo Ellis , Meyer Christian G. , Thye Thorsten , Niemann Stefan , Warren Robin M. , Streicher Elizabeth , Möller Marlo , Kinnear Craig 
Published: July 2020

AbstractDespite decades of research and advancements in diagnostics and treatment, tuberculosis remains a major public health concern, particularly in low- and middle-income countries. New bioinformatics and computational methods are needed to interrogate the intersection of host- and bacterial genomes and identify novel targets for anti-tuberculosis drugs. Host genotype datum and paired infecting bacterial isolate information were analysed for associations using a multinomial logistic regression framework implemented in SNPTest. Two geographically distinct cohorts were evaluated: a cohort of 947 participants self-identifying as belonging to a five-way admixed South African population and a Ghanaian cohort consisting of 3 311 participants. We report potential associations between host genetic variants and multiple members of the Mycobacterium tuberculosis complex (MTBC). Although none of the variants analyzed in the South African cohort passed the GWAS cut-off for significance, 32 single nucleotide polymorphisms were identified in the Ghanaian cohort as being statistically significantly associated with risk for infection with strains of different members of the MTBC. Further analysis revealed that two of these SNPs were directly genotyped, and the rest were imputed using the 1000 Genomes Phase 3 reference panel. The availability of paired host-pathogen data is imperative for investigating strain-specific interactions between MTBC and its host. As demonstrated by this study, the implementation of a multinomial logistic regression using paired host-pathogen data may prove valuable for further research investigating the complex relationships driving infectious disease.
Metabolomics differentiate cancer from non-cancer pleural effusions based on steroid lipids and acyl carnitines
Authors: Love Katie , da Costa Ricardo MF , Beckmann Manfred , Morley Anna , Bhatnagar Rahul , Maskell Nick , Mur Luis AJ , Lewis Keir E 
Published: July 2020

AbstractObjectiveTo identify and detect metabolomic markers to differentiate cancer related from other pleural effusions.Material and methodsUn-targeted flow infusion electrospray mass spectrometry was used on a cohort of 100 samples from benign and malignant pleural effusions (12 primary lung cancers, 14 mesotheliomas, 24 other cancers, 25 congestive cardiac failure, 22 parapneumonic effusion, 3 empyema). Standard metabolomic statistical models for analysis were performed.ResultsFive novel markers were identified using univariate and multivariate receiving operator curve analyses using five discriminant features yielding a diagnostic accuracy of above 0.91 (95% CI: 0.839-0.976) with a sensitivity of 0.97 (95% CI 0.952-0.979) and specificity 0.87 (95% CI 0.852-0.894).ConclusionIndividual biomarkers with the highest accuracy (>0.84) were all raised in cancer and are involved in metabolism of sterol-lipids and acyl carnitines linked to β-oxidation. Our markers performed better than those previously published. Further, these published markers failed to achieve their stated accuracies in our data.
Whence the next pandemic? The intersecting global geography of the animal-human interface, poor health systems and air transit centrality reveals conduits for high-impact spillover
Authors: Walsh Michael G. , Sawleshwarkar Shailendra , Hossain Shah , Mor Siobhan M. 
Published: July 2020

AbstractThe health and economic impacts of infectious disease pandemics are catastrophic as most recently manifested by coronavirus disease 2019 (COVID-19). The emerging infections that lead to substantive epidemics or pandemics are typically zoonoses that cross species boundaries at vulnerable points of animal-human interface. The sharing of space between wildlife and humans, and their domesticated animals, has dramatically increased in recent decades and is a key driver of pathogen spillover. Increasing animal-human interface has also occurred in concert with both increasing globalisation and failing health systems, resulting in a trifecta with dire implications for human and animal health. Nevertheless, to date we lack a geographical description of this trifecta that can be applied strategically to pandemic prevention. This investigation provides the first geographical quantification of the intersection of animal-human interfaces, poor human health system performance and global connectivity via the network of air travel. In so doing, this work provides a systematic, data-driven approach to classifying spillover hazard based on the distribution of animal-human interfaces while simultaneously identifying globally connected cities that are adjacent to these interfaces and which may facilitate global pathogen dissemination. We present this geography of high-impact spillover as a tool for developing targeted surveillance systems and improved health infrastructure in vulnerable areas that may present conduits for future pandemics.
TASK-3 Two-Pore Potassium Channels drive neuronal excitability of the circadian clock and entrainment to challenging light environments
Authors: Steponenaite Aiste , Lalic Tatjana , Atkinson Lynsey , Wei Liting , Mathie Alistair , Cader M. Zameel , Lall Gurprit S. 
Published: July 2020

AbstractThe suprachiasmatic nucleus (SCN), the mammalian circadian clock, is a heterogenous structure made of several neuron types that generate a circadian electrical activity profile. However, it is unclear how such regulation in endogenous neuronal excitability is maintained. Background two-pore domain potassium channels (K2P), such as TASK-3, play an important role in inhibiting neuronal activity. Here, we utilize a TASK-3 KO mouse model to unravel the role played by this channel in SCN circadian neuronal regulation and behavioral photoentrainment. Our results reveal that TASK-3 is needed to adapt to challenging lighting conditions, such as those experienced through seasonal changes and jet lag. From our investigations this appears to be very distinct from pathways that drive acute, ‘one-off’ adjustments in clock phase, in response to single pulses of light. These findings provide crucial information on the intricate pathways linking clock output to behavioral adaptation to light-dark cycles.
Single cell visualisation ofmir-9aandSenselessco-expression duringDrosophila melanogasterembryonic and larval peripheral nervous system development
Authors: Gallicchio Lorenzo , Griffiths-Jones Sam , Ronshaugen Matthew 
Published: July 2020

AbstractTheDrosophila melanogasterperipheral nervous system (PNS) comprises the sensory organs that allow the fly to detect environmental factors such as temperature and pressure. PNS development is a highly specified process where each sensilla originates from a single sensory organ precursor (SOP) cell. One of the major genetic orchestrators of PNS development isSenseless, which encodes a zinc finger transcription factor (Sens). Sens is both necessary and sufficient for SOP differentiation.Senselessexpression and SOP number are regulated by the microRNAmiR-9a. However, the reciprocal dynamics ofSenselessandmiR-9aare still obscure. By coupling smFISH with immunofluorescence, we are able to visualize transcription of themir-9alocus and expression of Sens simultaneously. During embryogenesis, we show that the expression ofmir-9ain SOP cells is rapidly lost asSenselessexpression increases. However, this mutually exclusive expression pattern is not observed in the third instar imaginal wing disc, where someSenseless-expressing cells show active sites ofmir-9atranscription. These data challenge and extend previous models ofSenselessregulation, and show complex co-expression dynamics betweenmir-9aandSenseless. The differences in this dynamic relationship between embryonic and larval PNS development suggest a possible switch inmiR-9afunction. Our work brings single-cell resolution to the understanding of dynamic regulation of PNS development bySenselessandmiR-9a.
Effects of constitutive and acute Connexin 36 deficiency on brain-wide susceptibility to PTZ-induced neuronal hyperactivity
Authors: Brunal Alyssa A. , Clark Kareem C. , Ma Manxiu , Pan Y. Albert 
Published: July 2020

ABSTRACTConnexins are transmembrane proteins that form hemichannels allowing the exchange of molecules between the extracellular space and cell interior. Two hemichannels from adjacent cells dock and form a continuous gap junction pore, thereby permitting direct intercellular communication. Connexin 36 (Cx36), expressed primarily in neurons, is involved in the synchronous activity of neurons and may play a role in aberrant synchronous firing, as seen in seizures. To understand the reciprocal interactions between Cx36 and seizure-like neural activity, we examined three questions: a) does Cx36 deficiency affect seizure susceptibility, b) does seizure-like activity affect Cx36 expression patterns, and c) does acute blockade of Cx36 conductance increase seizure susceptibility. We utilize the zebrafish pentylenetetrazol (PTZ; a GABA(A) receptor antagonist) induced seizure model, taking advantage of the compact size and optical translucency of the larval zebrafish brain to assess how PTZ affects brain-wide neuronal activity and Cx36 protein expression. We exposed wild-type and genetic Cx36-deficient (cx35.5- /-) zebrafish larvae to PTZ and subsequently mapped neuronal activity across the whole brain, using phosphorylated extracellular-signal-regulated kinase (pERK) as a proxy for neuronal activity. We found thatcx35.5-/-fish exhibited region-specific susceptibility and resistance to PTZ-induced hyperactivity compared to wild-type controls, suggesting that genetic Cx36 deficiency may affect seizure susceptibility in a region-specific manner. Regions that showed increased PTZ sensitivity include the dorsal telencephalon, which is implicated in human epilepsy, and the lateral hypothalamus, which has been underexplored. We also found that PTZ-induced neuronal hyperactivity resulted in a rapid reduction of Cx36 protein levels. 30 minutes and one-hour exposure to 20 mM PTZ significantly reduced the expression of Cx36. This Cx36 reduction persists after one-hour of recovery but recovered after 3-6 hours. This acute downregulation of Cx36 by PTZ is likely maladaptive, as acute pharmacological blockade of Cx36 by mefloquine results in increased susceptibility to PTZ-induced neuronal hyperactivity. Together, these results demonstrate a reciprocal relationship between Cx36 and seizure-associated neuronal hyperactivity: Cx36 deficiency contributes region-specific susceptibility to neuronal hyperactivity, while neuronal hyperactivity-induced downregulation of Cx36 may increase the risk of future epileptic events.
Automated prediction and annotation of small proteins in microbial genomes
Authors: Durrant Matthew G. , Bhatt Ami S. 
Published: July 2020

AbstractRecent work performed by Sberro et al. (2019) revealed a vast unexplored space of small proteins existing within the human microbiome. At present, these small open reading frames (smORFs) are unannotated in existing reference genomes and standard genome annotation tools are not able to accurately predict them. In this study, we introduce an annotation tool namedSmORFinderthat predicts small proteins based on those identified by Sberro et al. This tool combines profile Hidden Markov models (pHMMs) of each small protein family and deep learning models that may better generalize to smORF families not seen in the training set. We find that combining predictions of both pHMM and deep learning models leads to more precise smORF predictions and that these predicted smORFs are enriched for Ribo-Seq or MetaRibo-Seq translation signals. Feature importance analysis reveals that the deep learning models learned to identify Shine-Dalgarno sequences, deprioritize the wobble position in each codon, and group codons in a way that strongly corresponds to the codon synonyms found in the codon table. We perform a core genome analysis of 26 bacterial species and identify many core smORFs of unknown function. We pre-compute small protein annotations for thousands of RefSeq isolate genomes and HMP metagenomes, and we make these data available through a web portal along with other useful tools for small protein annotation and analysis. The systematic identification and annotation of those important small proteins will help researchers to expand our understanding of this exciting field of biology.
Antibodies that potently inhibit or enhance SARS-CoV-2 spike protein-ACE2 interaction isolated from synthetic single-chain antibody libraries
Authors: Beasley Matthew D. , Aracic Sanja , Gracey Fiona M. , Kannan Ruban , Masarati Avisa , Premaratne S. R. , Udawela Madhara , Wood Rebecca E. , Jabar Shereen , Church Nicole L. , Le Thien-Kim , Makris Dahna , McColl Bradley K. , Kiefel Ben R. 
Published: July 2020

AbstractAntibodies with high affinity against the receptor binding domain (RBD) of the SARS-CoV-2 S1 ectodomain were identified from screens using the Retained Display™ (ReD) platform employing a 1 × 1011clone single-chain antibody (scFv) library. Numerous unique scFv clones capable of inhibiting binding of the viral S1 ectodomain to the ACE2 receptorin vitrowere characterized. To maximize avidity, selected clones were reformatted as bivalent diabodies and monoclonal antibodies (mAb). The highest affinity mAb completely neutralized live SARS-CoV-2 virus in cell culture for four days at a concentration of 6.7 nM, suggesting potential therapeutic and/or prophylactic use. Furthermore, scFvs were identified that greatly increased the interaction of the viral S1 trimer with the ACE2 receptor, with potential implications for vaccine development.
Neural synchrony predicts children’s learning of novel words
Authors: Piazza Elise A. , Cohen Ariella , Trach Juliana , Lew-Williams Casey 
Published: July 2020

AbstractSocial interactions have a well-studied influence on early development and language learning. Recent work has begun to investigate the neural mechanisms that underlie shared representations of input, documenting neural synchrony or coupling (measured using intersubject temporal correlations of neural activity) between individuals exposed to the same stimulus. Neural synchrony has been found to predict the quality of engagement with a stimulus and with communicative cues, but studies have yet to address how neural synchrony among children may relate to real-time learning. Using functional near-infrared spectroscopy (fNIRS), we recorded the neural activity of 45 children (3.5-4.5 years) during joint book reading with an adult experimenter. The custom children’s book contained four novel words and objects embedded in an unfolding story, as well as a range of narrative details about object functions and character roles. We observed synchronized neural activity between child participants during book reading and found a positive correlation between learning and intersubject neural synchronization in parietal cortex, an area implicated in narrative-level processing in adult research. Our findings suggest that children’s learning is facilitated by active neural engagement with the dynamics of natural social input.
Cortical Silent Period reflects individual differences in action stopping performance
Authors: Paci Mario , Di Cosmo Giulio , Perrucci Mauro Gianni , Ferri Francesca , Costantini Marcello 
Published: July 2020

AbstractInhibitory control is the ability to suppress inappropriate movements and unwanted actions, allowing to regulate impulses and responses. This ability can be measured via the Stop Signal Task, which provides a temporal index of response inhibition, the stop signal reaction time (SSRT). At the neural level, Transcranial Magnetic Stimulation (TMS) allows to investigate of motor inhibition within the primary motor cortex (M1), such as the Cortical Silent period (CSP). CSP’s length is an index of GABAB-mediated intracortical inhibition within M1. Although there is strong evidence that intracortical inhibition varies during action stopping, it is still not clear whether differences in the neurophysiological markers of intracortical inhibition contribute to behavioral differences in actual inhibitory capacities. Hence, we here explored the relationship between intracortical inhibition within M1 and behavioral response inhibition. GABABergic-mediated inhibition in M1 was determined by the length of CSP, while behavioral inhibition was assessed by the SSRT. We found a significant positive correlation between CSP’s length and SSRT, namely that individuals with greater levels of GABABergic-mediated inhibition seem to perform overall worse in inhibiting behavioral responses. These results support the assumption that individual differences in intracortical inhibition are mirrored by individual differences in action stopping abilities.
How scars shape the neural landscape: key molecular mediators of TGF-β1’s anti-neuritogenic effects
Authors: Jeon Kye-Im , Huxlin Krystel R. 
Published: July 2020

AbstractFollowing injury to the peripheral and central nervous systems, tissue levels of transforming growth factor (TGF)-β1 often increase, which is key for wound healing and scarring. However, active wound regions and scars appear to inhibit process outgrowth by regenerating neurons. We recently showed that corneal wound myofibroblasts block corneal nerve regenerationin vivo, and sensory neurite outgrowthin vitroin a manner that relies critically on TGF-β1. In turn, delayed, abnormal re-innervation contributes to long-term sensory dysfunctions of the ocular surface. Here, we exposed morphologically and biochemically-differentiated sensory neurons from the ND7/23 cell line to TGF-β1 to identify the intracellular signals regulating these anti-neuritogenic effects, contrasting them with those of Semaphorin(Sema)3A, a known inhibitor of neurite outgrowth. Neuronal morphology was quantified using phase-contrast imaging. Western blotting and specific inhibitors were then used to identify key molecular mediators. Differentiated ND7/23 cells expressed neuron-specific markers, including those involved in neurite extension and polarization. TGF-β1 increased phosphorylation of collapsin response mediator protein-2 (CRMP2), a molecule that is key for neurite extension. We now show that both glycogen synthase kinase (GSK)-3β and Smad3 modulate phosphorylation of CRMP2 after treatment with TGF-β1. GSK-3β appeared to exert a particularly strong effect, which could be explained by its ability to phosphorylate not only CRMP2, but also Smad3. In conclusion, TGF-β1’s inhibition of neurite outgrowth in sensory neurons appears to be regulated through a highly-conserved signaling pathway, which involves the GSK-3β/CRMP-2 loop via both canonical and non-canonical mechanisms. It is hoped that by defining the signaling pathways that control neurite outgrowth in wound environments, it will become possible to identify optimal molecular targets to promote re-innervation following injury.