bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Isolated Presentation of Ischemic Retinal Vasculitis by the Great Masquerader
Authors: Lim Yi Wen , Lott Pooi Wah , Mohamad Nor Fadhilah , Samsudin Amir , Singh Sujaya , Iqbal Tajunisah 
Published: December 2020

Abstract
Ischemic retinal vasculitis is a sight-threatening inflammatory ocular condition that involves the retinal blood vessels. It is often associated with vascular occlusion and retinal hypoperfusion that may lead to neovascularization and subsequently preretinal and vitreous hemorrhages. It can be idiopathic or secondary to infection, neoplasia, or any other systemic diseases. Although it is rare, tuberculosis, which is an airborne disease caused by Mycobacterium tuberculosis, can manifest as retinal vasculitis without any evidence of pulmonary or other ocular structures involvement.
We present a case of a 16-year-old girl with sudden blurred vision in the right eye. Based on fundoscopic examination and fluorescein fundus angiography, the right eye had severe bilateral ischemic vasculitis and neovascularization. Both Mantoux and tuberculosis spot test (T-Spot) further supported the presumptive clinical diagnosis of ocular tuberculous ischemic retinal vasculitis. Subsequently, pan-retinal photocoagulation sessions were commenced together with antituberculosis therapy and resulted in improved vision. We also include a literature review of similar reported cases where occlusive retinal vasculitis is the only presentation of ocular tuberculosis. Although this case highlights the possibility of ischemic retinal vasculitis as the only feature of ocular tuberculosis, a high degree of suspicion is necessary when dealing with this great masquerader.
Generalization of placebo pain relief
Authors: Kampermann Lea , Tinnermann Alexandra , Büchel Christian 
Published: December 2020

Abstract
Efficacy of treatment is heavily dependent on experience and expectations. Moreover, humans can generalize from one experience to a perceptually similar but novel situation. We investigated whether and how this applies to pain relief, using ecologically valid tonic pain stimuli treated by surreptitiously lowering the applied temperature. Using different face cues, participants experienced better treatment from one physician than another. Participants were then tested on 6 additional face cues perceptually lying between both faces. Our data from 2 independent samples (N = 18 and N = 39) show a treatment experience effect, ie, for physically identical treatments, the initially superior physician was reported to deliver stronger pain relief. More importantly, the other faces on the perceptual continuum showed a graded effect of pain relief, indicating placebo generalization. Introducing a paradigm feasible to induce placebo pain relief, we show that the generic learning principle of generalization can explain carryover effects between learned and novel treatment situations.
Beyond botulinum neurotoxin A for chemodenervation of the bladder
Authors: Thaker Hatim , Zhang Sicai , Diamond David A. , Dong Min 
Published: December 2020

Purpose of review
Botulinum neurotoxin A (BoNT/A), or Botox, is a popular option for overactive bladder (OAB) and neurogenic bladder (NGB) with or without incontinence. This review aims to discuss the clinical outcomes of BoNT in adult and pediatric bladder conditions, and introduces the potential benefit of novel, engineered neurotoxins beyond BoNT/A.

Recent findings
A large volume of evidence supports the use of Botox for OAB (to reduce urgency, frequency and incontinence episodes), and for NGB (to decrease incontinence and improve bladder capacity and detrusor pressures). Botox is now also Food & Drug Administration (FDA)-approved for pediatric neurogenic detrusor overactivity. However, urinary retention, diminished response over time and treatment failures are prevalent issues with Botox. Modifying natural BoNTs or forming chimeric toxins are alternatives to BoNT/A that may have higher efficacy and lower side-effect profile. One example is BoNT/BMY-WW. This novel engineered toxin binds to a more commonly expressed synaptotagmin receptor, with potentially more potent paralytic effect and less capacity for systemic diffusion.

Summary
Novel engineered neurotoxins may be the next frontier in OAB and NGB therapy.
Meta-Analysis of Allergy Genome-Wide Association Studies
Authors: Sharma Ronin 
Published: December 2020

AbstractAllergies are complex conditions involving both environmental and genetic factors. The genetic basis underlying allergic disease is investigated through genetic association studies. Genome-wide association studies (GWAS) leverage sequenced data to identify genetic mutations, such as single-nucleotide polymorphisms (SNPs), associated with phenotypes of interest. Machine learning can be used to analyze large datasets and generate predictive models. In this study, several classification models were created to predict the significance level of SNPs associated with allergies. Summary statistics were obtained from the GWAS Catalog and combined from several studies. Biological features such as chromosomal location, base pair location, effect allele, and odds ratio were used to train the models. The models ranged from simple linear regressions to multi-layer neural networks. The final models reached accuracies of 80% and reflect the features that have the largest impact on a SNP’s association level.
MHC-II constrains the natural neutralizing antibody response to the SARS-CoV-2 spike RBM in humans
Authors: Castro Andrea , Ozturk Kivilcim , Zanetti Maurizio , Carter Hannah 
Published: December 2020

AbstractSARS-CoV-2 antibodies develop within two weeks of infection, but wane relatively rapidly post-infection, raising concerns about whether antibody responses will provide protection upon re-exposure. Here we revisit T-B cooperation as a prerequisite for effective and durable neutralizing antibody responses centered on a mutationally constrained RBM B cell epitope. T-B cooperation requires co-processing of B and T cell epitopes by the same B cell and is subject to MHC-II restriction. We evaluated MHC-II constraints relevant to the neutralizing antibody response to a mutationally-constrained B cell epitope in the receptor binding motif (RBM) of the spike protein. Examining common MHC-II alleles, we found that peptides surrounding this key B cell epitope are predicted to bind poorly, suggesting a lack MHC-II support in T-B cooperation, impacting generation of high-potency neutralizing antibodies in the general population. Additionally, we found that multiple microbial peptides had potential for RBM cross-reactivity, supporting previous exposures as a possible source of T cell memory.Graphical abstract
Functional MRI based simulations of ECoG grid configurations for optimal measurement of spatially distributed hand-gesture information
Authors: van den Boom Max , Miller Kai J. , Ramsey Nick F. , Hermes Dora 
Published: December 2020

AbstractIn electrocorticography (ECoG), the physical characteristics of the electrode grid determine which aspect of the neurophysiology is measured. For particular cases, the ECoG grid may be tailored to capture specific features, such as in the development and use of brain-computer-interfaces (BCI). Neural representations of hand movement are increasingly used to control ECoG based BCIs. However, it remains unclear which grid configurations are the most optimal to capture the dynamics of hand gesture information. Here, we investigate how the design and surgical placement of grids would affect the usability of ECoG measurements. High resolution 7T functional MRI was used as a proxy for neural activity in ten healthy participants to simulate various grid configurations, and evaluated the performance of each configuration for decoding hand gestures. The grid configurations varied in number of electrodes, electrode distance and electrode size. Optimal decoding of hand gestures occurred in grid configurations with a higher number of densely-packed, large-size, electrodes up to a grid of~5×5 electrodes. When restricting the grid placement to a highly informative region of primary sensorimotor cortex, optimal parameters converged to about 3×3 electrodes, an inter-electrode distance of 8mm, and an electrode size of 3mm radius (performing at~70% 3-class classification accuracy). Our approach might be used to identify the most informative region, find the optimal grid configuration and assist in positioning of the grid to achieve high BCI performance for the decoding of hand-gestures prior to surgical implantation.
Feasibility and safety of a telemetric pulmonary artery pressure monitoring system in acute and chronic porcine models of pulmonary hypertension
Authors: Rothman Alexander M. K. , Arnold Nadine D. , Abou-Hanna Jacob , Forouzan Omid , Swift Andrew J. , Dahaghin Payman , Konganige Shiran , Middleton Jennifer T. , Zafar Hamza , Suvarna S. Kim , Kiely David G , Gunn Julian 
Published: December 2020

AbstractAimsPulmonary hypertension (PH) is associated with significant morbidity and mortality and leads to progressive right heart failure. In patients with PAH, haemodynamic parameters measured at catheterisation relate to clinical worsening events, in patients with heart failure proactive pulmonary artery pressure based therapeutic intervention reduces hospitalisation. We therefore investigated use of a novel implanted pulmonary artery (PA) pressure monitor to detect clinically relevant changes in pressure in large animal models of pulmonary hypertension (PH).Methods and ResultsPrototype pulmonary artery pressure sensors (Endotronix) were implanted using standard interventional techniques. Acute PH was induced by infusion of thromboxane A2 in domestic swine. Over a physiological range pressure monitors remained concordant to reference catheter (bias −0.43, 95%CI-5.3-4.4). Chronic PH was induced by i.p. injection of monocrotaline. Implanted pressure sensors demonstrated a gradual rise in PA pressure over 30 days (baseline: 20.7+/-0.4 vrs day-30: 31.74+/-1.4, p<0.01). Pressure sensor derived readings matched reference catheter at baseline and day-30. Pressure sensors remained stable and no adverse events were identified by clinical and histological examination.ConclusionsThe development of PA pressure monitors provide long-term haemodynamic data that identified clinically meaningful changes in pulmonary artery pressure. In addition to proactive heart failure management, such devices may be used to optimise or personalize patient therapy, investigate aspects of physiology and pathology essential to the understanding of disease and provide the opportunity to assess therapeutic interventions in clinical studies.
Age-related Impairment of Implant Osseointegration is Associated with Immune Activation and Suppression of Angiogenic, Notch, and Wnt Pathways
Authors: Turajane Kathleen , Ji Gang , Chinenov Yurii , Chao Max , Ayturk Ugur , Greenblatt Matthew B. , Ivashkiv Lionel B. , Bostrom Mathias PG. , Yang Xu 
Published: December 2020

ABSTRACTThe number of total joint replacements (TJRs) in the United States is increasing annually. Cementless implants are intended to improve upon traditional cemented implants by allowing bone growth directly on the surface to improve implant longevity. One major complication of TJR is implant loosening, which is related to deficient osseointegration in cementless TJRs. Although poor osseointegration in aged patients is typically attributed to decreased basal bone mass, little is known about the molecular pathways that compromise the growth of bone onto porous titanium implants. To identify the pathways important for osseointegration that are compromised by aging, we developed an approach for transcriptomic profiling of peri-implant tissue in young and aged mice using our murine model of osseointegration. Based on previous findings of changes of bone quality associated with aging, we hypothesized that aged mice have impaired activation of bone anabolic pathways at the bone-implant interface. We found that pathways most significantly downregulated in aged mice relative to young mice are related to angiogenic, Notch and Wnt signaling. Downregulation of these pathways is associated with markedly increased expression of inflammatory and immune genes at the bone-implant interface in aged mice. These results identify osseointegration pathways affected by aging and suggest that an increased inflammatory response in aged mice may compromise peri-implant bone healing. Targeting the Notch and Wnt pathways, promoting angiogenesis, or modulating the immune response at the peri-implant site may enhance osseointegration and improve the outcome of joint replacement in older patients.
Dispensability of the second Cys for phycoviolobilin formation by unusual ring D fixation in the cyanobacteriochrome
Authors: Fushimi Keiji , Narikawa Rei 
Published: December 2020

AbstractCyanobacteriochromes are linear tetrapyrrole-binding photoreceptors produced by cyanobacteria. Their chromophore-binding GAF domains are categorized into many lineages. Among them, the DXCF cyanobacteriochrome GAF domains have a “second Cys” within the DXCF motif in addition to a highly conserved “first Cys” stably ligated to C31of the A-ring. It has been long known that the second Cys is crucial for two color-tuning events: isomerization activity (reduction of C4=C5 double bond) from the initially incorporated phycocyanobilin to phycoviolobilin and reversible ligation activity to the C10 of the chromophore. Comprehensive site-directed mutagenesis, however, revealed that the second Cys is dispensable for isomerization activity, in which three residues participate by fixing the C- and D-rings. Fixation of the chromophore on both sides of the C5 bridge is necessary, even though one side of the fixation site is far from this bridge, with the other side at C31fixed by the first Cys.
The autophagy activator Spermidine ameliorates Alzheimer’s disease pathology and neuroinflammation in mice
Authors: Freitag Kiara , Sterczyk Nele , Schulz Julia , Houtman Judith , Fleck Lara , Sigrist Stephan J. , Heppner Frank L. , Jendrach Marina 
Published: December 2020

AbstractDeposition of amyloid beta (Aβ) and phosphorylated Tau along with microglia- and astrocyte-mediated neuroinflammation are prominent pathogeneic features of Alzheimer’s Disease (AD). In recent years, impairment of autophagy has also been shown to contribute to AD progression. Here, we provide evidence that oral treatment of amyloid-prone AD-like APPPS1 mice with the autophagy activator Spermidine, a small body-endogenous polyamine often used as dietary supplement, decreased neuroinflammation and reduced neurotoxic soluble Aβ at both early and late stages of AD. Mechanistically, Spermidine induced autophagy in microglia as well as in astrocytes, which subsequently impacted TLR3- and TLR4-mediated inflammatory processes by decreasing cytotoxicity, inflammasome activity and NF-κB signalling. Our data highlight that autophagy targets the inflammatory response of glial cells and emphasize the potential of orally administered autophagy-activating drugs such as Spermidine to interfere with AD progression.
Molecular and functional properties of PFC astrocytes during neuroinflammation-induced anhedonia
Authors: Diaz-Castro Blanca , Bernstein Alexander M. , Coppola Giovanni , Sofroniew Michael V. , Khakh Baljit S. 
Published: December 2020

AbstractAstrocytes are widely implicated in CNS diseases, but their contributions to disease related phenotypes remain incompletely explored. Anhedonia accompanies several neurological and psychiatric diseases, including major depressive disorder (MDD) and Alzheimer’s disease (AD), both of which are associated with neuroinflammation. In order to explore how neuroinflammation affects astrocytes, we assessed medial prefrontal cortex (PFC) and visual cortex (VCX) astrocytic gene expression using a neuroinflammation mouse model that displayed anhedonia as a phenotype. In this model, anhedonia was reversed by the fast acting antidepressant ketamine. Astrocyte specific gene expression alterations included those related to immune cell signaling, intracellular Ca2+signaling, cholesterol biosynthesis, and metabolic pathways. Such changes peaked when anhedonia was greatest, and reversed to normal when anhedonia subsided. However, region-specific molecular identities between PFC and VCX astrocytes were maintained throughout, implying that astrocyte identities do not converge during neuroinflammation. We also mapped anhedonia-related astrocyte and bulk tissue gene expression changes onto published PFC single cell RNA sequencing data, and compared them to MDD and AD post-mortem human tissue samples to identify shared mechanisms. Finally, we assessed how neuroinflammation affected mPFC neuronal properties and detected no alterations at a time point when there was strong astrocyte reactivity. Our data show that neuroinflammation can cause significant and reversible changes in astrocyte gene expression and mouse behaviour without obvious neurotoxicity or loss of essential homeostatic functions. Furthermore, gene expression signatures accompanying neuroinflammation reveal pathways shared with MDD and AD, which display neuroinflammation as a comorbidity in humans.Significance statementAstrocytes are widely implicated in brain diseases, but their contributions to disease-related phenotypes remain incompletely explored. To make inroads into this problem, we assessed medial prefrontal cortex (PFC) and visual cortex (VCX) astrocyte gene expression using a peripherally induced neuroinflammation mouse model that produced anhedonia – a phenotype associated with several brain disorders. Neuroinflammation caused reversible changes in mouse behaviour and astrocyte-specific gene expression changes, some of which were related to human post mortem data for major depressive disorder (MDD) and Alzheimer’s disease (AD), but without any clear evidence of neurotoxicity in PFC of mice. The astrocyte molecular alterations accompanying neuroinflammation-induced anhedonia will be informative to explore diverse brain disorders and the effects of neuroinflammation on the CNS more broadly.
Single cell gene fusion detection by scFusion
Authors: Jin Zijie , Huang Wenjian , Shen Ning , Li Juan , Wang Xiaochen , Park Peter J. , Xi Ruibin 
Published: December 2020

AbstractGene fusions are widespread in tumor cells and can play important roles in tumor initiation and progression. Using full length single cell RNA sequencing (scRNA-seq), gene fusions can now be detected at single cell level. However, scRNA-seq data has a high noise level and contains various technical artefacts that can lead to spurous fusion discoveries. Here we present a computational tool, scFusion, for gene fusion detection based on scRNA-seq. scFusion can efficiently and sensitively detect fusions with a low false discovery rate. In a T cell data, scFusion detected the invariant TCR gene recombinations in Mucosal-associated invariant T cells that many methods developed for bulk-data failed to detect. In a multiple myeloma data, scFusion detected the known recurrent fusionIgH-WHSC1, which was associated with overexpression of theWHSC1oncogene.
An in vivo CRISPR screening platform for prioritizing therapeutic targets in AML
Authors: Lin Shan , Larrue Clément , Seong Bo Kyung A. , Dharia Neekesh V. , Kuljanin Miljan , Wechsler Caroline , Kugener Guillaume , Robichaud Amanda , Conway Amy , Mashaka Thelma N. , Mouche Sarah , Adane Biniam , Ryan Jeremy , Mancias Joseph D. , Younger Scott T. , Piccioni Federica , Lee Lynn , Wunderlich Mark , Letai Anthony , Tamburini Jérôme , Stegmaier Kimberly 
Published: December 2020

AbstractCRISPR-Cas9-based genetic screens have successfully identified cell type-dependent liabilities in cancers, including acute myeloid leukemia (AML), a devastating hematologic malignancy with poor overall survival. Because most of these screens have been performed in vitro, evaluating the physiological relevance of these targets is critical. We have established a CRISPR screening approach using orthotopic xenograft models to prioritize AML-enriched dependencies in vivo, complemented by the validation in CRISPR-competent AML patient-derived xenograft (PDX) models tractable for genome editing. Our integrated pipeline has revealed several targets with translational value, includingSLC5A3as a metabolic vulnerability for AML addicted to exogenous myo-inositol andMARCH5as a critical guardian to prevent apoptosis in AML. MARCH5 repression enhanced the efficacy of BCL2 inhibitors such as venetoclax, highlighting the clinical potential of targetingMARCH5in AML. Our study provides a valuable strategy for discovery and prioritization of new candidate AML therapeutic targets.Statement of significanceThere is an unmet need to improve the clinical outcome of AML. We developed an integrated in vivo screening approach to prioritize and validate AML dependencies with high translational potential. We identifiedSLC5A3as a metabolic vulnerability andMARCH5as a critical apoptosis regulator in AML, representing novel therapeutic opportunities.
SARS-CoV-2 escapein vitrofrom a highly neutralizing COVID-19 convalescent plasma
Authors: Andreano Emanuele , Piccini Giulia , Licastro Danilo , Casalino Lorenzo , Johnson Nicole V. , Paciello Ida , Monego Simeone Dal , Pantano Elisa , Manganaro Noemi , Manenti Alessandro , Manna Rachele , Casa Elisa , Hyseni Inesa , Benincasa Linda , Montomoli Emanuele , Amaro Rommie E. , McLellan Jason S. , Rappuoli Rino 
Published: December 2020

ABSTRACTTo investigate the evolution of SARS-CoV-2 in the immune population, we co-incubated authentic virus with a highly neutralizing plasma from a COVID-19 convalescent patient. The plasma fully neutralized the virus for 7 passages, but after 45 days, the deletion of F140 in the spike N-terminal domain (NTD) N3 loop led to partial breakthrough. At day 73, an E484K substitution in the receptor-binding domain (RBD) occurred, followed at day 80 by an insertion in the NTD N5 loop containing a new glycan sequon, which generated a variant completely resistant to plasma neutralization. Computational modeling predicts that the deletion and insertion in loops N3 and N5 prevent binding of neutralizing antibodies. The recent emergence in the United Kingdom and South Africa of natural variants with similar changes suggests that SARS-CoV-2 has the potential to escape an effective immune response and that vaccines and antibodies able to control emerging variants should be developed.One Sentence SummaryThree mutations allowed SARS-CoV-2 to evade the polyclonal antibody response of a highly neutralizing COVID-19 convalescent plasma.