bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sacral Neuromodulation Lead Twisting Causes Migration and Loss of Efficacy
Authors: Guzman-Negron Juan M. , Derisavifard Samir , Goldman Howard B. 
Published: February 2020

Objective
This study aimed to present 2 cases with unusual lead complications in InterStim devices implanted in patients with refractory overactive bladder symptoms.

Materials
Two patients with InterStim implants presented with loss of efficacy. Both patients required lead revision surgery with findings of a twisted lead with associated lead migration.

Results
In both cases, revision surgery revealed twisting of the InterStim lead causing retrograde lead displacement. Patients were managed with lead removal and placement of a new lead. At the time of revision, one patient had a seroma within a large pocket of the implantable pulse generator (IPG) site, which was managed with closure and development of a new IPG pocket. In both cases, revision with new lead placement resulted in significant symptom improvement.

Conclusions
Sacral neuromodulation lead complications are known to be among the most consequential adverse events. We report the first 2 cases, to our knowledge, of patients presenting with an InterStim device that lost efficacy due to lead twisting and subsequent retrograde lead migration, likely due to rotation of the IPG within the gluteal pocket. This finding is easily remedied with IPG pocket revision and lead replacement.
Linking mechanisms of periodontitis to Alzheimer's disease
Authors: Sadrameli Mahtab , Bathini Praveen , Alberi Lavinia 
Published: February 2020

Purpose of review
The review article discusses the association between periodontal disease and the development of dementia.

Recent findings
In the last decade, increasing evidence has pointed to a microbial and inflammatory origin for Alzheimer's disease with the discovery of oral and airway bacteria, viruses, and fungal species in the brain of patients with Alzheimer's disease. Furthermore, recognized as the culprit of neural network dysfunction, β-amyloid oligomeric species have antimicrobial properties reinforcing the idea that dysbiosis in the host–microbiota interaction can be at the origin of dementia. Periodontitis (gum disease), a persistent low-grade inflammatory condition, caused by pathogenic microorganisms, has been linked to an increased β-amyloid burden and cognitive disabilities later in life.

Summary
The pathogens of periodontal disease and the subsequent chronic inflammatory responses have significant implications on the development of Alzheimer's disease. The exact molecular mechanism by which Porphyromonas gingivalis and periodontal disease are involved in the pathogenicity of Alzheimer's disease is not currently evident. Understanding this causality can be instrumental in the development of treatments for this yet uncurable disease.
Rapid Detection of Novel Coronavirus (COVID-19) by Reverse Transcription-Loop-Mediated Isothermal Amplification
Authors: Lamb Laura E. , Bartolone Sarah N. , Ward Elijah , Chancellor Michael B. 
Published: February 2020

AbstractNovel Corona virus (COVID-19 or 2019-nCoV) is an emerging global health concern that requires a rapid diagnostic test. Quantitative reverse transcription PCR (qRT-PCR) is currently the standard for COVID-19 detection; however, Reverse Transcription Loop-Mediated Isothermal Amplification (RT-LAMP) may allow for faster and cheaper field based testing at point-of-risk. The objective of this study was to develop a rapid screening diagnostic test that could be completed in under 30 minutes. Simulated patient samples were generated by spiking serum, urine, saliva, oropharyngeal swabs, and nasopharyngeal swabs with a portion of the COVID-19 nucleic sequence. The samples were tested using RT-LAMP as well as by conventional qRT-PCR. Specificity of the RT-LAMP was evaluated by also testing against other related coronaviruses. RT-LAMP specifically detected COVID-19 in simulated patient samples. This test was performed in under 30 minutes. This approach could be used for monitoring of exposed individuals or potentially aid with screening efforts in the field and potential ports of entry.
Genome-scale metabolic rewiring to achieve predictable titers rates and yield of a non-native product at scale
Authors: Banerjee Deepanwita , Eng Thomas , Lau Andrew K. , Wang Brenda , Sasaki Yusuke , Herbert Robin A. , Chen Yan , Liu Yuzhong , Prahl Jan-Philip , Singan Vasanth R. , Tanjore Deepti , Petzold Christopher J. , Keasling Jay D. , Mukhopadhyay Aindrila 
Published: February 2020

AbstractAchieving high titer rates and yields (TRY) remains a bottleneck in the production of heterologous products through microbial systems, requiring elaborate engineering and many iterations. Reliable scaling of engineered strains is also rarely addressed in the first designs of the engineered strains. Both high TRY and scale are challenging metrics to achieve due to the inherent trade-off between cellular use of carbon towards growthvs.target metabolite production. We hypothesized that being able to strongly couple product formation with growth may lead to improvements across both metrics. In this study, we use elementary mode analysis to predict metabolic reactions that could be targeted to couple the production of indigoidine, a sustainable pigment, with the growth of the chosen host,Pseudomonas putidaKT2440. We then filtered the set of 16 predicted reactions using -omics data. We implemented a total of 14 gene knockdowns using a CRISPRi method optimized forP. putidaand show that the resulting engineeredP. putidastrain could achieve high TRY. The engineered pairing of product formation with carbon use also shifted production from stationary to exponential phase and the high TRY phenotype was maintained across scale. In one design cycle, we constructed an engineeredP. putidastrain that demonstrates close to 50% maximum theoretical yield (0.33 g indigoidine/g glucose consumed), reaching 25.6 g/L indigoidine and a rate of 0.22g/l/h in exponential phase. These desirable phenotypes were maintained from batch to fed-batch cultivation mode, and from 100ml shake flasks to 250 mL ambr® and 2 L bioreactors.
Hyper-connectivity of the striatum related to restricted and repetitive behaviors’ severity in children with ASD
Authors: Dupong Irene , Di Martino Adriana 
Published: February 2020

AbstractRestricted and repetitive behaviors (RRB) are a core feature of autism spectrum disorder (ASD). But little is known about the underlying neurobiology of the disorder, preventing from having specific therapeutic targets. Based on the literature, we explored the correlates between a clinical score of RRB, using the Repetitive Behaviour Scale – Revised, and the intrinsic connectivity of seven striatal regions in a sample of 157 children with ASD. The sample was acquired from the ABIDE consortium. We found a significant correlation between the severity of our clinical scale and several cortico-striatal networks. Specifically, stronger connections were found between striatal seeds and two cortical areas, an occipital area and a frontal area in the left hemisphere. Intrinsic functional connectivity of the striatum could serve as a potential biomarker for improved detection of RRB severity.
Loss of graded enemy recognition in a Whitehead population allopatric with brood parasitic Long-tailed Cuckoos
Authors: Lawson Shelby L. , Leuschner Nora , Gill Brian J. , Enos Janice K. , Hauber Mark E. 
Published: February 2020

ABSTRACTMany avian hosts of brood parasitic birds discriminate between different types of threats and may respond with categorically different, specifically anti-predatory or anti-parasitic behaviors. Alternatively, hosts may adjust their responses to threat level in a graded manner, responding more aggressively to brood parasites during the laying and incubation stages of nesting, when nests are most susceptible to parasitism, and more aggressively to nest predators during the nestling and fledgling stages when predation would be more costly than parasitism. In New Zealand, endemic host Whiteheads act inconspicuously around their nests in the presence of sympatric Long-tailed Cuckoos, their obligate brood parasite, perhaps to avoid disclosing nest location. We tested behavioral responses of a Whitehead population on Tiritiri Matangi Island that has been breeding allopatrically from cuckoos for 17 years. We presented models of the allopatric parasite, a sympatric predator (Morepork Owl), and a sympatric non-threatening heterospecific (Song Thrush) during the egg and chick stages, and to groups of cooperatively breeding Whiteheads. We compared responses across nest stage and stimulus type. We found that, unlike sympatric Whiteheads elsewhere in New Zealand, Whiteheads on Tiritiri Matangi produced alarm calls in response to the cuckoo model. Furthermore, the rate of alarm calling was similar towards the cuckoo and the owl and across egg and chick stage and higher than to the control stimulus. These results are consistent with allopatric Whiteheads having lost their specific anti-parasitic defense tactics in response to brood parasitic cuckoos.
Simple post-translational circadian clock models from selective sequestration
Authors: Byrne Mark 
Published: February 2020

AbstractIt is possible that there are post-translational circadian oscillators that continue functioning in the absence of negative feedback transcriptional repression in many cell types from diverse organisms. Apart from the KaiABC system from cyanobacteria, the minimal molecular components and interactions required to potentially create “test-tube” circadian oscillations in different cell types are currently unknown. Inspired by the KaiABC system, I provide proof-of-principle mathematical models that a protein with 2 (or more) modification sites which selectively sequesters an effector/cofactor molecule can function as a circadian time-keeper. The 2-site mechanism can be implemented using two relatively simple coupled non-linear ODEs in terms of site occupancy; the models do not require overly special fine-tuning of parameters for generating stable limit cycle oscillations.
In silico integration of thousands of epigenetic datasets into 707 cell type regulatory annotations improves the trans-ethnic portability of polygenic risk scores
Authors: Amariuta Tiffany , Ishigaki Kazuyoshi , Sugishita Hiroki , Ohta Tazro , Matsuda Koichi , Murakami Yoshinori , Price Alkes L. , Kawakami Eiryo , Terao Chikashi , Raychaudhuri Soumya 
Published: February 2020

AbstractPoor trans-ethnic portability of polygenic risk score (PRS) models is a critical issue that may be partially due to limited knowledge of causal variants shared among populations. Hence, leveraging noncoding regulatory annotations that capture genetic variation across populations has the potential to enhance the trans-ethnic portability of PRS. To this end, we constructed a unique resource of 707 cell-type-specific IMPACT regulatory annotations by aggregating 5,345 public epigenetic datasets to predict binding patterns of 142 cell-type-regulating transcription factors across 245 cell types. With this resource, we partitioned the common SNP heritability of diverse polygenic traits and diseases from 111 GWAS summary statistics of European (EUR, average N=180K) and East Asian (EAS, average N=157K) origin. For 95 traits, we were able to identify a single IMPACT annotation most strongly enriched for trait heritability. Across traits, these annotations captured an average of 43.3% of heritability (se = 13.8%) with the top 5% of SNPs. Strikingly, we observed highly concordant polygenic trait regulation between populations: the same regulatory annotations captured statistically indistinguishable SNP heritability (fitted slope = 0.98, se = 0.04). Since IMPACT annotations capture both large and consistent proportions of heritability across populations, prioritizing variants in IMPACT regulatory elements may improve the trans-ethnic portability of PRS. Indeed, we observed that EUR PRS models more accurately predicted 21 tested phenotypes of EAS individuals when variants were prioritized by key IMPACT tracks (49.9% mean relative increase in R2). Notably, the improvement afforded by IMPACT was greater in the trans-ethnic EUR-to-EAS PRS application than in the EAS-to-EAS application (47.3% vs 20.9%, P < 1.7e-4). Overall, our study identifies a crucial role for functional annotations such as IMPACT to improve the trans-ethnic portability of genetic data, and this has important implications for future risk prediction models that work across populations.
High-throughput cellular-resolution synaptic connectivity mappingin vivowith concurrent two-photon optogenetics and volumetric Ca2+imaging
Authors: McRaven Christopher , Tanese Dimitrii , Zhang Lixia , Yang Chao-Tsung , Ahrens Misha B. , Emiliani Valentina , Koyama Minoru 
Published: February 2020

AbstractThe ability to measure synaptic connectivity and properties is essential for understanding neuronal circuits. However, existing methods that allow such measurements at cellular resolution are laborious and technically demanding. Here, we describe a system that allows such measurements in a high-throughput way by combining two-photon optogenetics and volumetric Ca2+imaging with whole-cell recording. We reveal a circuit motif for generating fast undulatory locomotion in zebrafish.
Inhibitory parvalbumin basket cell activity is selectively reduced during hippocampal sharp wave ripples in a mouse model of familial Alzheimer’s disease
Authors: Caccavano Adam , Bozzelli P. Lorenzo , Forcelli Patrick A. , Pak Daniel T.S. , Wu Jian-Young , Conant Katherine , Vicini Stefano 
Published: February 2020

AbstractMemory disruption in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) is poorly understood, particularly at early stages preceding neurodegeneration. In mouse models of AD, there are disruptions to sharp wave ripples (SWRs), hippocampal population events with a critical role in memory consolidation. However, the micro-circuitry underlying these disruptions is under-explored. We tested if a selective reduction in parvalbumin-expressing (PV) inhibitory interneuron activity underlies hyperactivity and SWR disruption. We employed the 5xFAD model of familial AD crossed with mouse lines labeling excitatory pyramidal cells (PCs) and inhibitory PV cells. We observed a 33% increase in frequency, 58% increase in amplitude, and 8% decrease in duration of SWRs inex vivoslices from male and female 3-month 5xFAD mice versus littermate controls. 5xFAD mice of the same age were impaired in a hippocampal-dependent memory task. Concurrent with SWR recordings, we performed calcium imaging, cell-attached, and whole-cell recordings of PC and PV cells within the CA1 region. PCs in 5xFAD mice participated in enlarged ensembles, with superficial PCs having a higher probability of spiking during SWRs. Both deep and superficial PCs displayed an increased synaptic E/I ratio, suggesting a disinhibitory mechanism. In contrast, we observed a 46% spike rate reduction during SWRs in PV basket cells (PVBCs), while PV bistratified and axo-axonic cells were unimpaired. Excitatory synaptic drive to PVBCs was selectively reduced by 50%, resulting in decreased E/I ratio. Considering prior studies of intrinsic PV cell dysfunction in AD, these findings suggest alterations to the PC-PVBC micro-circuit also contribute to impairment.Significance StatementWe demonstrate that a specific sub-type of inhibitory neuron, parvalbumin-expressing basket cells, have selectively reduced activity in a model of Alzheimer’s disease during activity critical for the consolidation of memory. These results identify a potential cellular target for therapeutic intervention to restore aberrant network activity in early amyloid pathology. While parvalbumin cells have previously been identified as a potential therapeutic target, this study for the first time recognizes that other parvalbumin neuronal sub-types, including bistratified and axo-axonic cells, are spared. These experiments are the first to record synaptic and spiking activity during sharp wave ripple events in early amyloid pathology and reveal that a selective decrease in excitatory synaptic drive to parvalbumin basket cells likely underlies reduced function.
An autoimmune disease risk variant has atransmaster regulatory effect mediated by IRF1 under immune stimulation
Authors: Brandt Margot , Kim-Hellmuth Sarah , Ziosi Marcello , Gokden Alper , Wolman Aaron , Lam Nora , Recinos Yocelyn , Hornung Veit , Schumacher Johannes , Lappalainen Tuuli 
Published: February 2020

AbstractFunctional mechanisms remain unknown for most genetic loci associated to complex human traits and diseases. In this study, we first mappedtrans-eQTLs in a data set of primary monocytes stimulated with LPS, and discovered that a risk variant for autoimmune disease, rs17622517 in an intron ofC5ORF56, affects the expression of the transcription factorIRF120 kb away. The cis-regulatory effect onIRF1is active under early immune stimulus, with a large number oftrans-eQTL effects across the genome under late LPS response. Using CRISPRi silencing, we showed that the SNP locus indeed functions as anIRF1enhancer with widespread transcriptional effects. Genome editing by CRISPR further indicated that rs17622517 is indeed a causal variant in this locus, and recapitulated the LPS-specifictrans-eQTL signal. Our results suggest that this common genetic variant affects inter-individual response to immune stimuli via regulation ofIRF1. For this autoimmune GWAS locus, our work provides evidence of the causal variant, demonstrates a condition-specific enhancer effect, identifiesIRF1as the likely causal gene incis, and indicates that overactivation of the downstream immune-related pathway may be the cellular mechanism increasing disease risk. This work not only provides rare experimental validation of a master-regulatorytrans-eQTL, but also demonstrates the power of eQTL mapping to build mechanistic hypotheses amenable for experimental follow-up using the CRISPR toolkit.
Divergence, gene flow and the origin of leapfrog geographic distributions: The history of color pattern variation inPhyllobatespoison-dart frogs
Authors: Márquez Roberto , Linderoth Tyler P. , Mejía-Vargas Daniel , Nielsen Rasmus , Amézquita Adolfo , Kronforst Marcus R. 
Published: February 2020

AbstractThe geographic distribution of phenotypic variation among closely related populations is a valuable source of information about the evolutionary processes that generate and maintain biodiversity. Leapfrog distributions, in which phenotypically similar populations are disjunctly distributed and separated by one or more phenotypically distinct populations, represent geographic replicates for the existence of a phenotype, and are therefore especially informative. These geographic patterns have mostly been studied from phylogenetic perspectives to understand how common ancestry and divergent evolution drive their formation. Other processes, such as gene flow between populations, have not received as much attention. Here we investigate the roles of divergence and gene flow between populations in the origin and maintenance of a leapfrog distribution inPhyllobatespoison frogs. We found evidence for high levels of gene flow between neighboring populations but not over long distances, indicating that gene flow between populations exhibiting the central phenotype may have a homogenizing effect that maintains their similarity, and that introgression between “leapfroging” taxa has not played a prominent role as a driver of phenotypic diversity inPhyllobates. Although phylogenetic analyses suggest that the leapfrog distribution was formed through independent evolution of the peripheral (i.e. leapfrogging) populations, the elevated levels of gene flow between geographically close populations poise alternative scenarios, such as the history of phenotypic change becoming decoupled from genome-averaged patterns of divergence, which we cannot rule out. These results highlight the importance of incorporating gene flow between populations into the study of geographic variation in phenotypes, both as a driver of phenotypic diversity and as a confounding factor of phylogeographic inferences.
Ovarian Cancer Risk Variants are Enriched in Histotype-Specific Enhancers that Disrupt Transcription Factor Binding Sites
Authors: Jones Michelle R. , Peng Pei-Chen , Coetzee Simon G. , Tyrer Jonathan , Reyes Alberto L. , de la Fuente Rosario I. Corona , Davis Brian , Chen Stephanie , Dezem Felipe , Seo Ji-Heui ,   Ovarian Cancer Association Consortium, Berman Benjamin P. , Freedman Matthew L. , Plummer Jasmine T. , Lawrenson Kate , Pharoah Paul , Hazelett Dennis J. , Gayther Simon A. 
Published: February 2020

AbstractQuantifying the functional effects of complex disease risk variants can provide insights into mechanisms underlying disease biology. Genome wide association studies (GWAS) have identified 39 regions associated with risk of epithelial ovarian cancer (EOC). The vast majority of these variants lie in the non-coding genome, suggesting they mediate their function through the regulation of gene expression by their interaction with tissue specific regulatory elements (REs). In this study, by intersecting germline genetic risk data with regulatory landscapes of active chromatin in ovarian cancers and their precursor cell types, we first estimated the heritability explained by known common low penetrance risk alleles. The narrow sense heritabilityof both EOC overall and high grade serous ovarian cancer (HGSOCs) was estimated to be 5-6%. Partitioned SNP-heritability across broad functional categories indicated a significant contribution of regulatory elements to EOC heritability. We collated epigenomic profiling data for 77 cell and tissue types from public resources (Roadmap Epigenomics and ENCODE), and H3K27Ac ChIP-Seq data generated in 26 ovarian cancer-relevant cell types. We identified significant enrichment of risk SNPs in active REs marked by H3K27Ac in HGSOCs. To further investigate how risk SNPs in active REs influence predisposition to ovarian cancer, we used motifbreakR to predict the disruption of transcription factor binding sites. We identified 469 candidate causal risk variants in H3K27Ac peaks that break TF motifs (enrichment P-Value < 1×10−5compared to control variants). The most frequently broken motif was REST (P-Value = 0.0028), which has been reported as both a tumor suppressor and an oncogene. These systematic functional annotations with epigenomic data highlight the specificity of the regulatory landscape and demonstrate functional annotation of germline risk variants is most informative when performed in highly relevant cell types.