bluuebunny/crossref_metadata_2025_split huggingface dataset:
Does Compliance or Cost Regulate Effectiveness of Notched Sound Therapy Phone Applications for Tinnitus Relief? Preliminary Data of a Prospective Randomized Control Trial
Authors: Adamovich-Zeitlin Richard , Pelosi Stanley , Mullooly Virginia , Svrakic Maja 
Published: January 2023

Objective
The objective of this study is to evaluate compliance with and effectiveness of notched sound therapy (NST) administered through a mobile application in improving symptoms of patients experiencing chronic tinnitus.

Study Design
A prospective randomized control trial was done.

Setting
The study was done at a tertiary referral center.

Patients
Adult patients with tinnitus were monitored.

Interventions
Patients were randomized at enrollment to either the NST or a standard of care (SOC) group. NST arm included, in addition to SOC, a free subscription to NST mobile application, whereas the SOC arm included NST at subscription cost.

Main Outcome Measures
The main outcome measures were continued enrollment in study, compliance with the therapy, frequency and duration of therapy use, and change from the baseline in the Tinnitus Handicap Inventory (THI).

Results
Patients in the NST group were 2.25 times more likely to use the NST application for 3 months postenrollment. Only 33% of users in the NST group listened for the prescribed 2 h/d compared with 0% of users in the SOC group. There was a clinically relevant mean decrease in THI from a baseline of 13.5 in the NST group (p = 0.09) and of 14.8 in the SOC group (p = 0.02). There was a positive correlation between initial THI and decrease in THI after 3 months (p = 0.001).

Conclusions
Monitoring tinnitus for 3 months leads to a decrease in subjective symptoms regardless of NST use. Patients who received a free subscription to the application were more likely to continue with therapy, but very few patients were able to comply with 2 hours of listening time per day.
Reinventing Nuclear Histo-score Utilizing Inherent Morphologic Cutoffs: Blue-brown Color H-score (BBC-HS)
Authors: Price Phillipe , Ganugapati Usharani , Gatalica Zoran , Kakadekar Archan , Macpherson James , Quenneville Louise , Rees Henrike , Slodkowska Elzbieta , Suresh Janarthanee , Yu Darryl , Lim Hyun J. , Torlakovic Emina E. 
Published: January 2023

Immunohistochemistry (IHC) is a testing methodology that is widely used for large number of diagnostic, prognostic, and predictive biomarkers. Although IHC is a qualitative methodology, in addition to threshold-based stratification (positive vs. negative), the increasing levels of expression of some of these biomarkers often lead to more intense staining, which published evidence linked to specific diagnosis, prognosis, and responses to therapy. It is essential that the descriptive thresholds between positive and negative staining, as well as between frequently used graded categories of staining intensity (eg, 1+, 2+, 3+) are standardized and reproducible. Histo-score (H-score) is a frequently used scoring system that utilizes these categories. Our study introduces categorization of the cutoff points between positive and negative results and graded categories of staining intensity for nuclear IHC biomarker assays based on color interaction between hematoxylin and diaminobenzidine (DAB); the Blue-brown Color H-score (BBC-HS).
Six cases of diffuse large B-cell lymphoma were stained for a nuclear marker MUM1. The staining was assessed by H-score by 12 readers. Short tutorial and illustrated instructions were provided to readers. The novel scoring system in this study uses the interaction between DAB (DAB, brown stain) and hematoxylin (blue counterstain) to set thresholds between “0” (negative nuclei), “1+” (weakly positive nuclei), “2+” (moderately positive nuclei), and “3+” (strongly positive nuclei). The readers recorded scores for 300 cells. Krippendorff alpha (K-alpha) and intraclass correlation coefficient (ICC) were calculated. We have also assessed if reliability improved when counting the first 100 cells, first 200 cells, and for the total 300 cells using K-alpha and ICC. To assess the performance of each individual reader, the mean H-score and percent positive score (PPS) for each case was calculated, and the bias was calculated between each reader’s score and the mean.
K-alpha was 0.86 for H-score and 0.76 for PPS. ICC was 0.96 for H-score and 0.92 for PPS. The biases for H-score ranged from −58 to 41, whereas for PPS it ranged from −27% to 33%. Overall, most readers showed very low bias. Two readers were consistently underscoring and 2 were consistently overscoring compared with the mean. For nuclear IHC biomarker assays, our newly proposed cutoffs provide highly reliable/reproducible results between readers for positive and negative results and graded categories of staining intensity using existing morphologic parameters. BBC-HS is easy to teach and is applicable to both human eye and image analysis. BBC-HS application should facilitate the development of new reliable/reproducible scoring schemes for IHC biomarkers.
Early angiogenesis dependent CXCL12 attracts Adipose-derived stem cells to promote the repair of fat grafting in a mice model
Authors: Chen Yunzi , Wang Zijue , Li Ye , Li Bin , Wang Xinhui , Zou Jialiang , Bi Xin , Zhao Jing , Lu Feng , Dong Ziqing 
Published: January 2023

Background:
The unpredictable and unstable tissue retention rate of autologous fat grafting remains an obstacle faced by plastic surgeons. Our previous study using fat grafting mice model with donor site showed ASCs infiltration in recipient site was delayed, leading to poor regeneration and lower retention. Thus, the mechanism behind the differential infiltration of ASCs required to be explored.

Methods:
Firstly, we locally injected CXCL12 or CXCR4 inhibitor AMD3100 in recipient or donor site respectively (CXCL12+AMD3100-Group, CXCL12-AMD3100+Group, and CXCL12+AMD3100+Group). We compared the migration of ASCs, adipose regeneration and long-term retention. Next, we explored the role of angiogenesis using a Normal/Ischemic mice model in which we test the expression of CXCL12/CXCR4, migration of ASCs, and adipose regeneration.

Results:
Blocking CXCL12 in donor site using AMD3100 (CXCL12-AMD3100+, and CXCL12+AMD3100+Group) could accelerate ASCs infiltration, promote adipose regeneration and long-term retention (p<0.05) compared with the other groups. CXCL12 and its receptor CXCR4 expressed higher in Normal than in Ischemic adipose tissue; consistently, there were more ASCs infiltrating Normal than Ischemic adipose tissue early after surgery (p<0.05).

Conclusion:
Early angiogenesis is essential for CXCL12 in promoting ASCs infiltration, improving adipose tissue repair in recipient site and potentiating long-term fat retention rate.
Parasitic manipulation or side effects? The effects of pastToxoplasmaandBorreliainfections on human personality and cognitive performance are not mediated by impaired health
Authors: Flegr Jaroslav , Hlaváčová Jana , Toman Jan 
Published: January 2023

AbstractBacteriaBorrelia burgdorferi s. l. and even more the protozoanToxoplasma gondiiare known to affect the behavior of their animal and human hosts. Both pathogens infect a significant fraction of human population, and both survive in the host’s body for a long time. The resulting latent infections used to be considered clinically asymptomatic. In the last decade, however, numerous studies have shown that this view may be wrong and both infections can have various adverse effects on human health. Their specific behavioral effects may thus be merely side effects of the general impairment of patients’ health. We tested this hypothesis on a cohort of 7,762 members of internet population using a two-hour-long survey consisting of a panel of questionnaires and performance tests. Our findings confirmed that subjects infected withToxoplasmawere in worse physical and mental health and those infected withBorreliawere in worse physical health than corresponding controls. The infected and noninfected subjects also differed in several personality traits (conscientiousness, pathogen disgust, injury disgust, Machiavellianism, narcissism, tribalism, anti-authoritarianism, intelligence, reaction time, and precision). Majority of the behavioral effects associated withBorreliainfection were the same as those associated withToxoplasmainfection, but some dramatically differed (e.g., performance in the Stroop test). Path analyses and nonparametric partial Kendall correlation tests showed that these effects were not mediated by impaired health of the infected individuals. The results thus contradict predictions of the side effects hypothesis.
The ER folding sensor UGGT1 acts on TAPBPR-chaperoned peptide-free MHC I
Authors: Sagert Lina , Winter Christian , Ruppert Ina , Zehetmaier Maximilian , Thomas Christoph , Tampé Robert 
Published: January 2023

AbstractAdaptive immune responses are triggered by antigenic peptides presented on major histocompatibility complex class I (MHC I) at the surface of pathogen-infected or cancerous cells. Formation of stable peptide-MHC I complexes is facilitated by tapasin and TAPBPR, two related MHC I-specific chaperones that catalyze selective loading of suitable peptides onto MHC I in a process called peptide editing or proofreading. On their journey to the cell surface, MHC I complexes must pass a quality control step performed by UGGT1, which senses the folding status of the transiting N-linked glycoproteins in the endoplasmic reticulum (ER). UGGT1 reglucosylates non-native glycoproteins and thereby allows them to revisit the ER folding machinery. Here, we describe a reconstitutedin-vitrosystem of purified human proteins that enabled us to delineate the function of TAPBPR during the UGGT1-catalyzed quality control and reglucosylation of MHC I. By combining glycoengineering with liquid chromatography-mass spectrometry, we show that TAPBPR promotes reglucosylation of peptide-free MHC I by UGGT1. Thus, UGGT1 cooperates with TAPBPR in fulfilling a crucial function in the quality control mechanisms of antigen processing and presentation.
Bipolar anodal septal pacing with direct LBB capture preserves physiological ventricular activation better than unipolar left bundle branch pacing
Authors: Curila Karol , Jurak Pavel , Prinzen Frits , Jastrzebski Marek , Waldauf Petr , Halamek Josef , Tothova Marketa , Znojilova Lucie , Smisek Radovan , Kach Jakub , Poviser Lukas , Linkova Hana , Plesinger Filip , Moskal Pawel , Viscor Ivo , Vondra Vlastimil , Leinveber Pavel , Osmancik Pavel 
Published: January 2023

BackgroundLeft bundle branch pacing (LBBP) produces delayed, unphysiological activation of the right ventricle. Using ultra-high-frequency electrocardiography (UHF-ECG), we explored how bipolar anodal septal pacing with direct LBB capture (aLBBP) affects the resultant ventricular depolarization pattern.MethodsIn patients with bradycardia, His bundle pacing (HBP), unipolar nonselective LBBP (nsLBBP), aLBBP, and right ventricular septal pacing (RVSP) were performed. Timing of local ventricular activation, in leads V1-V8, was displayed using UHF-ECG, and electrical dyssynchrony (e-DYS) was calculated as the difference between the first and last activation. Durations of local depolarizations were determined as the width of the UHF-QRS complex at 50% of its amplitude.ResultsaLBBP was feasible in 63 of 75 consecutive patients with successful nsLBBP. aLBBP significantly improved interventricular dyssynchrony (−9 ms (−12;−6) vs. −24 ms (−27;−21),), p < 0.001) and shortened local depolarization durations in V1–V4 (mean differences −7 ms to −5 ms (−11;−1), p < 0.05) compared to nsLBBP. Both aLBBP and HBP caused similar absolute levels of interventricular dyssynchrony (e-DYS −9 ms (−12; −6) vs. 10 ms (7;14); however, local depolarization durations in V1–V2 during aLBBP were longer than HBP (differences 5–9 ms (1;14), p < 0.05, with local depolarization duration in V1 during aLBBP being the same as during RVSP (difference 2 ms (−2;6), p = 0.52).ConclusionAlthough aLBBP significantly improved interventricular synchrony and depolarization duration of the septum and RV compared to unipolar nsLBBP, the resultant ventricular depolarization was still less physiological than during HBP.
Analysis of recurrent research pathways for assessing and improving effectiveness in life sciences laboratories
Authors: Balas E. Andrew , Patel Charmi , Ewing Ben , Patel Nauka , Curry Tiana , Wise Scott , Abdelgawad Yara H 
Published: January 2023

ABSTRACTBackgroundLife sciences research often turns out to be ineffective. Our aim was to develop a method for mapping repetitive research processes, detecting practice variations, and exploring inefficiencies.MethodsThree samples of R&I projects were used: companion diagnostics of cancer treatments, identification of COVID-19 variants, and COVID-19 vaccine development. Major steps involved: defined starting points, desired end points; measurement of transition times and success rates; exploration of variations, and recommendations for improved efficiency.ResultsOver 50% of CDX developments failed to reach market simultaneously with new drugs. There were significant variations among phases of co-development (Bartlett test P<0.001). Length of time in vaccine development also shows variations (P<0.0001). Similarly, subject participation indicates unexplained variations in trials (Phase I: 489.7 (±461.8); Phase II: 857.3 (±450.1); Phase III: 35402 (±18079).ConclusionAnalysis of repetitive research processes can highlight inefficiencies and show ways to improve quality and productivity in life sciences.
Neutrophil extracellular trap stabilization by platelet factor 4 reduces thrombogenicity and endothelial cell injury
Authors: Ngo Anh T. P. , Sarkar Amrita , Yarovoi Irene , Levine Nate D. , Bochenek Veronica , Zhao Guohua , Rauova Lubica , Kowalska M. Anna , Eckart Kaitlyn , Mangalmurti Nilam S. , Rux Ann , Cines Douglas B. , Poncz Mortimer , Gollomp Kandace 
Published: January 2023

ABSTRACTNeutrophil extracellular traps (NETs) are abundant in sepsis, and proposed NET-directed therapies in sepsis prevent their formation or accelerate degradation. Yet NETs are important for microbial entrapment, as NET digestion liberates pathogens and NET degradation products (NDPs) that deleteriously promote thrombosis and endothelial cell injury. We proposed an alternative strategy of NET-stabilization with the chemokine, platelet factor 4 (PF4, CXCL4), which we have shown enhances NET-mediated microbial entrapment. We now show that NET compaction by PF4 reduces their thrombogenicity. In vitro, we quantified plasma thrombin and fibrin generation by intact or degraded NETs and cell-free (cf) DNA fragments, and found that digested NETs and short DNA fragments were more thrombogenic than intact NETs and high molecular weight genomic DNA, respectively. PF4 reduced the thrombogenicity of digested NETs and DNA by interfering, in part, with contact pathway activation. In endothelial cell culture studies, short DNA fragments promoted von Willebrand factor release and tissue factor expression via a toll-like receptor 9-dependent mechanism. PF4 blocked these effects.Cxcl4-/-mice infused with cfDNA exhibited higher plasma thrombin anti-thrombin (TAT) levels compared to wild-type controls. Following challenge with bacterial lipopolysaccharide,Cxcl4-/-mice had similar elevations in plasma TAT and cfDNA, effects prevented by PF4 infusion. Thus, NET-stabilization by PF4 prevents the release of short fragments of cfDNA, limiting the activation of the contact coagulation pathway and reducing endothelial injury. These results support our hypothesis that NET-stabilization reduces pathologic sequelae in sepsis, an observation of potential clinical benefit.HIGHLIGHTSIn contrast to intact NETs, degraded NETs and cfDNA are prothrombotic and injure the endothelium.PF4 reduces the ability of degraded NETs and cfDNA to promote thrombosis and injure the endothelium.
Low Rate Hippocampal Delay Period Activity Encodes Behavioral Experience
Authors: Athanasiadis Markos , Masserini Stefano , Yuan Li , Fetterhoff Dustin , Leutgeb Jill K , Leutgeb Stefan , Leibold Christian 
Published: January 2023

AbstractRemembering what just happened is a crucial prerequisite to form long-term memories but also for establishing and maintaining working memory. So far there is no general agreement about cortical mechanisms that support short-term memory. Using a classifier-based decoding approach, we report that hippocampal activity during few sparsely distributed brief time intervals contains information about the previous sensory motor experience of rodents. These intervals are characterized by only a small increase of firing rate of only a few neurons. These low-rate predictive patterns are present in both working memory and non-working memory tasks, in two rodent species, rats and Mongolian gerbils, are strongly reduced for rats with medial entorhinal cortex lesions, and depend on the familiarity of the sensory-motor context.
Statin-mediated reduction in mitochondrial cholesterol primes an anti-inflammatory response in macrophages by upregulating Jmjd3
Authors: Salloum Zeina , Dauner Kristin , Li Yun-fang , Verma Neha , Zhang John D. , Nakka Kiran , Chen Mei Xi , Valdivieso-González David , Almendro-Vedia Víctor , McDonald Jeffery , Corley Chase D. , Sorisky Alexander , Song Bao-Liang , López-Montero Iván , Luo Jie , Dilworth Jeffrey F. , Zha Xiaohui 
Published: January 2023

AbstractStains are known to be anti-inflammatory, but the mechanism remains poorly understood. Here we show that macrophages, either treated with statinin vitroor from statin-treated mice, have reduced cholesterol levels and higher expression ofJmjd3,a H3K27me3 demethylase. We provide evidence that lowering cholesterol levels in macrophages suppresses the ATP synthase in the inner mitochondrial membrane (IMM) and changes the proton gradient in the mitochondria. This activates NFκB andJmjd3expression to remove the repressive marker H3K27me3. Accordingly, the epigenome is altered by the cholesterol reduction. When subsequently challenged by the inflammatory stimulus LPS (M1), both macrophages treated with statinsin vitroor isolated from statin-treated micein vivo, express lower levels pro-inflammatory cytokines than controls, while augmenting anti-inflammatoryIl10expression. On the other hand, when macrophages are alternatively activated by IL4 (M2), statins promote the expression ofArg1,Ym1, andMrc1. The enhanced expression is correlated with the statin-induced removal of H3K27me3 from these genes prior to activation. In addition,Jmjd3and its demethylase activity are necessary for cholesterol to modulate both M1 and M2 activation. We conclude that upregulation ofJmjd3is a key event for the anti-inflammatory function of statins on macrophages.
Curation of causal interactions mediated by genes associated to autism accelerates the understanding of gene-phenotype relationships underlying neurodevelopmental disorders
Authors: Iannuccelli Marta , Vitriolo Alessandro , Licata Luana , Cheroni Cristina , Castagnoli Luisa , Testa Giuseppe , Cesareni Gianni , Perfetto Livia 
Published: January 2023

ABSTRACTAutism spectrum disorder (ASD) comprises a large group of neurodevelopmental conditions featuring, over a wide range of severity and combinations, a core set of manifestations (restricted sociality, stereotyped behavior and language impairment) alongside various comorbidities. Common and rare variants in several hundreds of genes and regulatory regions have been implicated in the molecular pathogenesis of ASD along a range of causation evidence strength. Despite significant progress in elucidating the impact of few paradigmatic individual loci, such sheer complexity in the genetic architecture underlying ASD as a whole has hampered the identification of convergent actionable hubs hypothesized to relay between the vastness of risk alleles and the core phenotypes. In turn this has limited the development of strategies that can revert or ameliorate this condition, calling for a systems-level approach to probe the cross-talk of cooperating genes in terms of causal interaction networks in order to make convergences experimentally tractable and reveal their clinical actionability. As a first step in this direction, we have captured from the scientific literature information on the causal links between the genes whose variants have been associated with ASD and the whole human proteome. This information has been annotated in a computer readable format in the SIGNOR database and is made freely available in the resource website. To link this information to cell functions and phenotypes, we have developed graph algorithms that estimate the functional distance of any protein in the SIGNOR causal interactome to phenotypes and pathways. The main novelty of our approach resides in the possibility to explore the mechanistic links connecting the suggested gene-phenotype relations.
Anti-seizure Gene Therapy for Focal Cortical Dysplasia
Authors: Barbanoj Amanda Almacellas , Graham Robert T. , Maffei Benito , Carpenter Jenna C. , Leite Marco , Hoke Justin , Hardjo Felisia , Scott-Solache James , Chimonides Christos , Schorge Stephanie , Kullmann Dimitri M. , Magloire Vincent , Lignani Gabriele 
Published: January 2023

AbstractFocal Cortical Dysplasias (FCDs) are a common subtype of malformation of cortical development, which frequently present with a spectrum of cognitive and behavioural abnormalities as well as pharmacoresistant epilepsy. FCD type II is typically caused by somatic mutations resulting in mTOR hyperactivity, and is the commonest pathology found in children undergoing epilepsy surgery. However, surgical resection does not always result in seizure freedom, and is often precluded by proximity to eloquent brain regions. Gene therapy is a promising potential alternative treatment and may be appropriate in cases that represent an unacceptable surgical risk. Here, we evaluated a gene therapy based on overexpression of the Kv1.1 potassium channel in a mouse model of frontal lobe FCD. An engineered potassium channel (EKC) transgene was placed under control of a human promoter that biases expression towards principal neurons (CAMK2A) and packaged in an adeno-associated viral vector (AAV9). We used an established FCD model generated byin uteroelectroporation of frontal lobe neural progenitors with a constitutively active humanRHEBplasmid, an activator of mTOR Complex 1. First, we further characterised this by quantifying electrocorticograms and behavioural abnormalities, both in mice developing spontaneous generalised seizures and in mice only exhibiting abnormal interictal discharges. Then, using continuous video-electrocorticogram recordings from epileptic mice before and after injection of AAV9-CAMK2A-EKC in the dysplastic region, we observed a robust decrease in the frequency of seizures and in interictal activity, compared to mice injected with a control viral vector. Despite the robust anti-epileptic effect of the treatment, there was neither an improvement nor a worsening of performance in behavioural tests sensitive to frontal lobe function. AAV9-CAMK2A-EKC had no effect on interictal activity or behaviour in non-epileptic mice. AAV9-CAMK2A-EKC gene therapy is a promising therapy with translational potential to treat the epileptic phenotype of mTOR-related malformations of cortical development. Cognitive and behavioural co-morbidities may, however, resist an intervention aimed at reducing circuit excitability.