bluuebunny/crossref_metadata_2025 huggingface dataset:
Lingual Tonsillectomy
Authors: Freeman Catherine , Hines Brittany , Hines John , Hoxworth Joseph , Wright Benjamin
Published: January 2021

Background

PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis) syndrome is diagnosed clinically. Adult-onset PFAPA syndrome is rare and often has a more diverse clinical presentation that its childhood counterpart. This is the first reported case of adult-onset PFAPA syndrome with complete response to lingual tonsillectomy.

Case Summary

A 41-year-old man was evaluated for periodic fevers associated with uvulitis, cervical lymphadenitis, pharyngitis, and lower extremity rash. He had a variable response to steroids and was intolerant of colchicine. Laboratory workup revealed intermittent elevation of erythrocyte sedimentation rate and C-reactive protein level. Computed tomography neck and laryngoscopy confirmed adenoidal and lingual tonsillar hypertrophy. He underwent adenoidectomy and lingual tonsillectomy with resolution of symptoms.

Conclusions

Hypertrophy of the remaining lymphoid structures within Waldeyer's ring may be associated with remote recurrence of PFAPA syndrome after tonsillectomy. Lingual tonsillectomy may be an alternative treatment strategy in select patients with PFAPA, prominent lingual hypertrophy, and incomplete response to steroids.
Long-Term Retention Rate of Golimumab in Patients With Rheumatoid Arthritis, Psoriatic Arthritis, and Spondyloarthritis in a Real-Life Setting
Authors: Serrano-Benavente Belén , Valor Larissa , del Río Blasco Tamara , Janta Iustina , González Benítez Roberto , Nieto-González Juan Carlos , Martínez-Barrio Julia , Ovalles Bonilla Juan Gabriel , Ariza Alfonso , López-Longo Francisco Javier , Álvaro-Gracia Jose María , Monteagudo Indalecio , González-Fernández Carlos Manuel
Published: January 2021

Objective

The aims of this study were to describe the long-term retention rate of golimumab (GLM) treatment in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondyloarthritis (SpA) in real life, and to analyze determinants of discontinuation.

Methods

We conducted a single-center, medical records review study of all patients with RA, PsA, and SpA on GLM treatment attending a large rheumatology department from 2010 to 2017. Times from start to end of GLM treatment were collected, as well as sociodemographic, clinical, and safety variables. Golimumab retention rate was estimated by the Kaplan-Meier method, and comparison across diseases was analyzed with the Mantel-Haenszel statistic (log-rank test). Cox proportional hazards regression models were used to identify factors associated with GLM discontinuation.

Results

In the study period, a total of 212 patients (61 RA, 48 PsA, 103 SpA) were prescribed GLM. Retention rates were 72% in the first year, 61% in the second, 56% in the third, and 38% at 5 years. Differences were statistically significant across diseases (median times to GLM discontinuation were 50.2, 46.0, and 38.7 months for RA, SpA, and PsA, respectively) and according to the number of previous biologic therapies (55.2 months in biologic-naive patients vs 14.0 months in patients with ≥2 previous biologics; p < 0.001). The use of concomitant conventional synthetic disease-modifying antirheumatic drugs was associated with a lower probability of discontinuation (hazards ratio [HR], 0.57; 95% confidence interval [CI], 0.33–0.97). Female sex (HR, 1.84; 95% CI, 1.07–3.17) and having used 2 biologics before GLM (HR, 2.99; 95% CI, 1.76–5.06) were associated with increased discontinuation rates. Twenty-three patients (10.9%) had at least 1 serious adverse event.

Conclusions

In a real-life setting, GLM shows appropriate long-term safety-effectiveness ratio.
Clinical Characteristics of Juvenile Idiopathic Inflammatory Myopathy and Comparison With Adult Patients
Authors: Loarce-Martos Jesús , Larena Carmen , Blázquez M. Ángeles , Joven Beatriz E. , Carreira Patricia E. , Martínez-Barrio Julia , Monteagudo Indalecio , López-Longo Francisco Javier , Ruiz Lucía , López-Robledillo Juan Carlos , Almodóvar Raquel , Llorente Irene , Tomero Eva , García-de la Peña Paloma , Moruno Henry , Pérez Ana , Cobo-Ibáñez Tatiana , Lojo Oliveira Leticia , Barbadillo María Carmen , García-De Yébenes María Jesús , Nuño-Nuño Laura
Published: January 2021

Background/Objective

Few studies have been published focusing on the differences between juvenile idiopathic inflammatory myopathy (JIIM) and adult IIM. This study aimed to describe the characteristics of JIIM main subgroups (juvenile dermatomyositis [JDM] and juvenile polymyositis [JPM]) and to compare their differences with adult IIM subgroups (adult DM and adult PM).

Methods

This study reviewed the medical records of patients from the REMICAM cohort, a multicentric longitudinal study carried out in patients with IIM, followed up between 1980 and 2014 in 12 hospitals in Madrid, Spain. Patients with definite or probable JPM, JDM, adult DM, and adult PM according to the modified Bohan and Peter criteria were selected. We compared the characteristics between JDM and JPM, and between JIIM and adult IIM.

Results

Eighty-six juvenile patients (75 JDMs and 11 JPMs) and 283 adult patients (133 DMs and 150 PMs) were included. Compared with patients with JDM, patients with JPM were older at diagnosis, had more fever and arthritis, and were less frequently treated with disease-modifying antirheumatic drugs (these differences were not statistically significant). Compared with patients with adult DM, those with JDM presented more frequently with calcinosis (33.8% vs 6.9%, p < 0.0001) and had less severe infections (4.3% vs 23.4%, p < 0.0001), malignancies (1.3% vs 25.6%, p < 0.0001), and mortality (3.5% vs 33%, p < 0.0001). Patients with JDM were treated less frequently with azathioprine (10.8% vs 44.7%, p < 0.0001).

Conclusions

Our findings confirm that JIIMs are a heterogeneous group of diseases with relevant differences compared with adult IIMs.
Cystic Lymph Node Identification Is More Reliable Than Critical View of Safety in Difficult Cholecystectomies
Authors: Ng Hwei J. , Nassar Ahmad H.M. , Wysocki Arkadiusz P. , Ahmed Zubir , Gil Ines C.
Published: January 2021

Background:

The cystic lymph node (CLN) represents an anatomic safety marker and a surrogate marker of technique during laparoscopic cholecystectomy (LC). We aim to demonstrate the value of CLN in comparison to the critical view of safety (CVS) and study the effects of increasing difficulty on the 2 approaches.

Methods:

A prospective study of consecutive LC was conducted. Patient demographics, type of admission, clinical presentation, operative difficulty grade, visualization of CLN, identification of CVS, operative time, and complications were recorded and analyzed.

Results:

Of 393 LCs, half of the admissions were emergencies. Thirty-four percent had obstructive jaundice or acute cholecystitis. The CLN was visually identified in 81.7% with a small difference between operative difficulty grades 1 to 3 versus 4 to 5. Although CVS was unachievable in 62 patients, 43 (69.4%) still had an identifiable CLN. The median operating time was 68 minutes with 1 mortality but no conversions or intraoperative complications.

Conclusions:

Identifying the CLN during LC could compliment the CVS in avoiding major ductal injury. Dissecting lateral to the CLN to commence the process of displaying the cystic pedicle structures may be a strategy in safely achieving the CVS. During the more difficult LC where displaying the CVS is impossible, the CLN may be the key anatomic landmark.
Retrograde Myotomy as an Alternative to Antegrade Myotomy in Peroral Endoscopic Myotomy (POEM) for Achalasia Cardia – Is It Better?
Authors: Mandavdhare Harshal S. , Samanta Jayanta , Jafra Anudeep , Chauhan Rajeev , Singh Harjeet , Kumar Naveen , Kumar Kimavat Hemanth , Gupta Pankaj , Dutta Usha , Kochhar Rakesh
Published: January 2021

Background:

Antegrade approach myotomy is usually performed in peroral endoscopic myotomy (POEM) for achalasia cardia. This study assessed the feasibility of retrograde approach as an alternative.

Methods:

This is a retrospective review of a prospectively maintained database of patients undergoing POEM, comparing the 2 techniques of antegrade myotomy (AM) and retrograde myotomy (RM). AM was performed by the conventional technique of proximal to distal myotomy while RM was from the distal end to proximal. The time required for myotomy, complications, and technical nuances were compared.

Results:

Of the 24 cases of POEM, 6 were done by RM and 18 by AM approach. The baseline characteristics, symptomatology, type of achalasia, and preprocedure Eckardt score were similar between the 2 technique arms. The median myotomy time for AM was 21 minute while for RM was 25 minute (P=0.07). Complication rates were similar.

Technical issues during RM included: (1) difficulty in visualizing the depth of myotomy; (2) incomplete myotomy requiring back and forth scope adjustment; (3) need for antegrade movement for completion of myotomy; (4) difficulty visualizing the axis of myotomy; (5) added arm strain during posterior myotomy.

Conclusion:

Our study did not find any additional benefit of RM compared with AM approach for POEM.
Comparison of Clinical Outcomes Between Laparoscopic and Open Extensive Resection for Complicated Appendicitis: Retrospective Observational Study
Authors: Takeyama Hiroshi , Ikeda Kimimasa , Shinomiya Satoshi , Nishigaki Takahiko , Yamashita Masafumi , Danno Katsuki , Taniguchi Hirokazu , Sugimoto Keishi , Oka Yoshio
Published: January 2021

Background:

The feasibility and safety of laparoscopic extensive resection (ER) for complicated appendicitis (CA) has not been clarified. We assessed the feasibility of laparoscopic ER versus open ER for CA.

Methods:

We retrospectively enrolled consecutive 983 patients who underwent emergency surgery for appendicitis, including 91 patients who underwent ER for CA, between April 2007 and October 2019.

Results:

Thirty-three patients underwent laparoscopic ER, and 58 patients underwent open ER. There were no significant differences in the reasons for performing ER between laparoscopic ER and open ER. The rates of suspicious for malignant tumor did not differ between laparoscopic and open ER [15.2% (5/33) vs. 17.2% (10/58)]. Blood loss was less in laparoscopic ER than in open ER (P=0.028). Superficial surgical site infection was less frequent in laparoscopic ER than in open ER (P=0.047). In addition, laparoscopic ER tended to be associated with a shorter hospital stay, lower rate of postoperative ileus, and higher rate of intra-abdominal abscess.

Conclusion:

Laparoscopic ER is feasible, and it is associated with less intraoperative blood loss and a lower frequency of postoperative superficial surgical site infection than open ER.
Nationwide cost-effectiveness analysis of surgical stabilization of rib fractures by flail chest status and age groups
Authors: Choi Jeff , Mulaney Bianca , Laohavinij Wasin , Trimble Richard , Tennakoon Lakshika , Spain David A. , Salomon Joshua A. , Goldhaber-Fiebert Jeremy D. , Forrester Joseph D.
Published: January 2021

BACKGROUND

Surgical stabilization of rib fracture (SSRF) is increasingly used to manage patients with rib fractures. Benefits of performing SSRF appear variable, and the procedure is costly, necessitating cost-effectiveness analysis for distinct subgroups. We aimed to assess the cost-effectiveness of SSRF versus nonoperative management among patients with rib fractures younger than 65 years versus 65 years or older, with versus without flail chest. We hypothesized that, compared with nonoperative management, SSRF is cost-effective only for patients with flail chest.

METHODS

This economic evaluation used a decision-analytic Markov model with a lifetime time horizon incorporating US population-representative inputs to simulate benefits and risks of SSRF compared with nonoperative management. We report quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios. Deterministic and probabilistic sensitivity analyses accounted for most plausible clinical scenarios.

RESULTS

Compared with nonoperative management, SSRF was cost-effective for patients with flail chest at willingness-to-pay threshold of US $150,000/QALY gained. Surgical stabilization of rib fracture costs US $25,338 and US $123,377/QALY gained for those with flail chest younger than 65 years and 65 years or older, respectively. Surgical stabilization of rib fracture was not cost-effective for patients without flail chest, costing US $172,704 and US $243,758/QALY gained for those younger than 65 years and 65 years or older, respectively. One-way sensitivity analyses showed that, under most plausible scenarios, SSRF remained cost-effective for subgroups with flail chest, and nonoperative management remained cost-effective for patients older than 65 years without flail chest. Probability that SSRF is cost-effective ranged from 98% among patients younger than 65 years with flail chest to 35% among patients 65 years or older without flail chest.

CONCLUSIONS

Surgical stabilization of rib fracture is cost-effective for patients with flail chest. Surgical stabilization of rib fracture may be cost-effective in some patients without flail chest, but delineating these patients requires further study.

LEVEL OF EVIDENCE

Economic/decision, level II.
Fascia-Focused Pilates for the Older Adult
Authors: Larkam Elizabeth
Published: January 2021

Age-related changes to the neuromyofascial system affect proprioception, reaction time, strength, balance, coordination, and gait. These changes diminish quality of life measures, the ability to perform activities of daily living, and physical independence. Fascia-focused Pilates for the older adult is a type of mindful movement. Fascia research findings are applied to the principles, equipment, and movement vocabulary of Joseph H. Pilates. This article suggests a movement sequence that improves the proprioception, balance, coordination, and gait for an 80-year-old female client.
SUMIC: A Simple Ultrafast Multicolor Immunolabelling and Clearing Approach for Whole-Organ and Large Tissue 3D Imaging
Authors: Biswas Lincoln , Chen Junyu , De Angelis Jessica , Chatzis Alexandros , Nanchahal Jagdeep , Dustin Michael L. , Ramasamy Saravana K. , Kusumbe Anjali P.
Published: January 2021

High-resolution whole-organ imaging of cleared tissues captures cellular and molecular insights within the intact tissue and tumour microenvironments. However, current immunolabelling and clearing methods are complicated and time-consuming; extending to several weeks. Here, we developedSimpleUltrafastMulticolorImmunolabelling andClearing orSUMIC, a method that enables multicolor immunolabelling and clearing of whole murine organs and human tissues within 2 to 2.5 days. Moreover, SUMIC is simple, robust, non-hazardous and versatile comprising antigen retrieval, permeabilization, collagenase-based digestion, immunolabelling, dehydration, and clearing. SUMIC permits quantitative and singlecell resolution analysis and detection of rare cells in whole organs, for example, round αSMA positive cells in the thymus. Upon volumetric imaging, SUMIC-processed samples retain normal tissue architecture and can be used for paraffin-embedding and histology. We employed the SUMIC method for whole-organ mapping of lymphatic vessels across different ages and organs. This analysis revealed the expansion of lymphatic vessels in endocrine tissues but not in any other organs with aging. Hence, SUMIC will accelerate discoveries compared to other whole organ imaging pipelines.
Queuine, a bacterial derived hypermodified nucleobase, shows protection inin vitromodels of neurodegeneration
Authors: Richard Patricia , Manière Xavier , Kozlowski Lucie , Guillorit Hélène , Garnier Patrice , Danchin Antoine , McKnight Nicole C.
Published: January 2021

Growing evidence suggests that human gut bacteria, comprising the microbiome that communicates with the brain through the so-called ‘gut-brain-axis’, are linked to neurodegenerative disorders. Imbalances in the microbiome of Parkinson’s disease (PD) and Alzheimer’s disease (AD) patients have been detected in several studies. Queuine is a hypermodified nucleobase enriched in the brain and exclusively produced by bacteria and salvaged by humans through their gut epithelium. Queuine replaces guanine at the wobble position of tRNAs with GUN anticodons and promotes efficient cytoplasmic and mitochondrial mRNA translation.

To elucidate whether queuine could facilitate protein folding and prevent aggregation and mitochondrial defects, hallmarks of neurodegenerative disorders, we tested the effect of chemically synthesized queuine, STL-101, in severalin vitromodels of neurodegeneration. Treatment with STL-101 led to increased neuronal survival as well as a significant decrease in hyper-phosphorylated alpha-synuclein, a marker of alpha-synuclein aggregation in a PD model and a decrease in tau hyperphosphorylation in an AD model. Our work has identified a new role for queuine in neuroprotection uncovering a therapeutic potential for STL-101 in neurological disorders.
Effects of Diabetes and Blood Glucose on COVID-19 Mortality: A Retrospective Observational Study
Authors: Li Fei , Cai Yue , Gao Chao , Zhou Lei , Chen Renjuan , Zhang Kan , Li Weiqin , Zhang Ruining , Zhang Xijing , Wang Duolao , Liu Yi , Tao Ling
Published: January 2021

OBJECTIVE

To investigate the association of diabetes and blood glucose on mortality of patients with Coronavirus Disease 2019 (COVID-19).

RESEARCH DESIGN AND METHODS

This was a retrospective observational study of all patients with COVID-19 admitted to Huo-Shen-Shan Hospital, Wuhan, China. The hospital was built only for treating COVID-19 and opened on February 5, 2020. The primary endpoint was all-cause mortality during hospitalization.

RESULTS

Among 2877 hospitalized patients, 13.5% (387/2877) had a history of diabetes and 1.9% (56/2877) died in hospital. After adjustment for confounders, patients with diabetes had a 2-fold increase in the hazard of mortality as compared to patients without diabetes (adjusted HR 2.11, 95%CI: 1.16-3.83, P=0.014). The on-admission glucose (per mmol/L≥4mmol/L) was significantly associated with subsequent mortality on COVID-19 (adjusted HR 1.17, 95%CI: 1.10-1.24, P<0.001).

CONCLUSIONS

Diabetes and on-admission glucose (per mmol/L≥4mmol/L) are associated with increased mortality in patients with COVID-19. These data support that blood glucose should be properly controlled for possibly better survival outcome in patients with COVID-19.
Discovery of μ, δ-Opioid receptor dual biased agonists that overcome the limitation of prior biased agonists
Authors: Lee Jin Hee , Shon Suh-Youn , Jeon Woojin , Hong Sung-Jun , Ban Junsu , Lee Do Sup
Published: January 2021

Morphine is widely used to manage pain in patients, although the risk of side effects is significant. The use of biased agonists to the G protein of μ-opioid receptors has been suggested as a potential solution, although Oliceridine and PZM21 have previously failed to demonstrate benefits in clinical studies. An amplification-induced confusion in the process of comparing G protein and beta-arrestin pathways may account for previous biased agonist mis-identification. Here, we have devised a strategy to discover biased agonists with intrinsic efficacy. We computationally simulated 430,000 molecular dockings to the μ-opioid receptor to construct a compound library. Hits were then verified by experiment. Using the verified compounds, we performed simulations to build a second library with a common scaffold, and selected compounds which show biased features to μ and δ-opioid receptors through a cell-based assay. Three compounds (ID110460001, ID110460002, and ID110460003) with a dual biased agonistic effect for μ and δ-opioid receptors were identified. These candidates are full agonists for the μ-opioid receptor, and they show specific binding modes. Based on our findings, we expect our novel compound to act as a biased agonist than conventional drugs such as Oliceridine.
QTL mapping: an innovative method for investigating the genetic determinism of yeast-bacteria interactions in wine
Authors: Bartle Louise , Peltier Emilien , Sundstrom Joanna , Sumby Krista , Mitchell James G , Jiranek Vladimir , Marullo Philippe
Published: January 2021

The two most commonly used wine microorganisms,Saccharomyces cerevisiaeyeast andOenococcus oenibacteria, are responsible for completion of alcoholic and malolactic fermentation (MLF), respectively. For successful co-inoculation,S. cerevisiaeandO. oenimust be able to complete fermentation, however, this relies on compatibility between yeast and bacterial strains. For the first time, Quantitative Trait Loci (QTL) analysis was used to elucidate whetherS. cerevisiaegenetic makeup can play a role in the ability ofO. oenito complete MLF. Assessment of 67 progeny of anS. cerevisiaeSBxGN cross, co-inoculated with a singleO. oenistrain, SB3, revealed a major QTL linked to MLF completion byO. oeni. This QTL encompassed a well-known translocation, XV-t-XVI, that results in increasedSSU1expression and is functionally linked with numerous phenotypes including lag phase duration and sulfite export and production. A reciprocal hemizygosity assay was performed to elucidate the effect of the geneSSU1in the SBxGN background. Our results instead revealed a strong effect ofSSU1haploinsufficiency onO. oeni’s ability to complete malolactic fermentation during co-inoculation, and paves the way for the implementation of QTL mapping projects for deciphering the genetic bases of microbial interactions.

Key points

For the first time QTL analysis has been used to study yeast-bacteria interactions.

A QTL encompassing a translocation, XV-t-XVI, was linked to MLF outcomes.

S. cerevisiae SSU1haploinsufficiency positively impacted MLF byO. oeni.
DINC-COVID: A webserver for ensemble docking with flexible SARS-CoV-2 proteins
Authors: Hall-Swan Sarah , Antunes Dinler A. , Devaurs Didier , Rigo Mauricio M. , Kavraki Lydia E. , Zanatta Geancarlo
Published: January 2021

Motivation

Recent efforts to computationally identify inhibitors for SARS-CoV-2 proteins have largely ignored the issue of receptor flexibility. We have implemented a computational tool for ensemble docking with the SARS-CoV-2 proteins, including the main protease (Mpro), papain-like protease (PLpro) and RNA-dependent RNA polymerase (RdRp).

Results

Ensembles of other SARS-CoV-2 proteins are being prepared and made available through a user-friendly docking interface. Plausible binding modes between conformations of a selected ensemble and an uploaded ligand are generated by DINC, our parallelized meta-docking tool. Binding modes are scored with three scoring functions, and account for the flexibility of both the ligand and receptor. Additional details on our methods are provided in the supplementary material.

Availability

dinc-covid.kavrakilab.org

Supplementary information

Details on methods for ensemble generation and docking are provided as supplementary data online.

Contact

geancarlo.zanatta@ufc.br,kavraki@rice.edu
Does plant –microbe’s common Inter Simple Sequence Repeat lead to a new recombination? A novel mechanism of pathogenicity
Authors: Rakhashiya Purvi M. , Bhatt Pritesh P. , Thaker Vrinda S.
Published: January 2021

A total of eight varieties of the mango from an orchard were studied using molecular markers to understand the host-pathogen interaction. From the infected leaves of the plant, a total of the 8 bacterial pathogens (Exiguobacterium arabatum, Pseudomonas mendocina, Pantoea dispersa, Bacillus sp. Pantoea ananatis, Micrococcous luteus, Microbacterium_sp., Enterobacter cloacae) were isolated and identified. All the host varieties of mango were distinguished for the genetic diversity using the Inter Simple Sequence Repeat (ISSR) DNA markers. This set of ISSR marker primers were also used for the mango pathogens. PCR amplification of the ISSR primers showed polymorphic and monomorphic band patterns in the host plants and in their pathogens. The monomorphic band generated by PCR amplification in the host and in the pathogen, by the common primer, is selected and used for PCR hybridization technique. PCR products obtained from the host, pathogen and hybridization were cloned, sequenced and compared. A multiple sequence alignment of these sequences revealed that the product of hybridization PCR was mixture of host and pathogen sequences. On this basis, we hypothesize a possibility for the recombination of host-microbes DNA as one of the mechanisms of pathogenicity for the plant pathogens using hybrid PCR technique. The possible mechanism of recombination for plant host and its pathogen is discussed.

Highlights

Inter Simple Sequence Repeat markers used to (i) Fingerprint the pathogens and their host (mango) and (ii) for study of the possibilities for the recombination as mechanism of pathogenicity.
Alzheimer’s disease-associated β-Amyloid does not protect against Herpes Simplex Virus 1 brain infection
Authors: Bocharova Olga , Molesworth Kara , Pandit Narayan P. , Baskakov Ilia V.
Published: January 2021

Alzheimer’s disease (AD) is devastating fatal neurodegenerative disease. An alternative to the amyloid cascade hypothesis is the hypothesis that a viral infection is key to the etiology of late-onset AD, with amyloid Aβ peptides playing a protective role. Contrary to previous work, in the current study the 5XFAD genotype failed to protect mice against infection with two strains of herpes simplex virus 1 (HSV-1), 17syn+ and McKrae. Moreover, the region- or cell-specific tropisms of HSV-1 were not affected by the 5XFAD genotype, arguing that host-pathogen interactions were not altered. In aged 5XFAD mice with abundant Aβ plaques, only small, statistically non-significant protection against acute HSV-1 infection was observed, yet no colocalization between HSV-1 and Aβ plaques was found. While the current study questions the antiviral role of APP or Aβ, it neither supports nor refutes the viral etiology hypothesis of late-onset AD.
Pancreatic cancer prognosis is predicted by a novel ATAC-array technology for assessing chromatin accessibility
Authors: Dhara S , Chhangawala S , Chintalapudi H , Askan G , Aveson V , Massa AL , Zhang L , Torres D , Makohon-Moore AP , Lecomte N , Melchor JP , Bermeo J , Cardenas A , Sinha S , Glassman D , Nicolle R , Moffitt R , Yu KH , Leppanen S , Laderman S , Curry B , Gui J , Balachandran VP , Iacobuzio-Donahue C , Chandwani R , Leslie CS , Leach SD
Published: January 2021

We investigated tumor-cell-intrinsic chromatin accessibility patterns of pancreatic ductal adenocarcinoma (PDAC) by ATAC-seq on EpCAM+PDAC malignant epithelial cells, sorted from 54 freshly resected human tumors, and discovered a signature of 1092 chromatin loci displaying differential accessibility between patients with disease free survival (DFS) < 1 year and patients with DFS > 1 year. Analyzing transcription factor (TF) binding motifs within these loci, we identified two TFs (ZKSCAN1 and HNF1b) displaying differential nuclear localization between patients with short vs. long DFS. We further developed a novel chromatin accessibility microarray methodology termed“ATAC-Array”, an easy-to-use platform obviating the time and cost of next generation sequencing. Applying this novel methodology to the original ATAC-seq libraries as well as independent libraries generated from patient-derived organoids, we validated ATAC-array technology in both the original ATAC-Seq cohort as well as in an independent validation cohort. We conclude that PDAC prognosis can be predicted by ATAC-array, which represents a novel, lowcost, clinically feasible technology for assessing chromatin accessibility profiles.
The expected behaviour of random fields in high dimensions: contradictions in the results of Bansal and Peterson (2018)
Authors: Davenport Samuel , Nichols Thomas E.
Published: January 2021

Bansal and Peterson (2018) found that in simple stationary Gaussian simulations Random Field Theory incorrectly estimates the number of clusters of a Gaussian field that lie above a threshold. Their results contradict the existing literature and appear to have arisen due to errors in their code. Using reproducible code we demonstrate that in their simulations Random Field Theory correctly predicts the expected number of clusters and therefore that many of their results are invalid.
A Single Cell Atlas of Lung Development
Authors: Negretti Nicholas M. , Plosa Erin J. , Benjamin John T. , Schuler Bryce A. , Habermann A. Christian , Jetter Christopher , Gulleman Peter , Taylor Chase J. , Nichols David , Matlock Brittany K. , Guttentag Susan H. , Blackwell Timothy S. , Banovich Nicholas E. , Kropski Jonathan A. , Sucre Jennifer M. S.
Published: January 2021

Lung organogenesis requires precisely timed shifts in the spatial organization and function of parenchymal cells, especially during the later stages of lung development. To investigate the mechanisms governing lung parenchymal dynamics during development, we performed a single cell RNA sequencing (scRNA-seq) time-series yielding 92,238 epithelial, endothelial, and mesenchymal cells across 8 time points from embryonic day 12 (E12) to postnatal day 14 (P14) in mice. We combined new computational analyses with RNAin situhybridization to explore transcriptional velocity, fate likelihood prediction, and spatiotemporal localization of cell populations during the transition between the saccular and alveolar stages. We interrogated this atlas to illustrate the complexity of type 1 pneumocyte function during the saccular and alveolar stages, and we demonstrate an integrated view of the cellular dynamics during lung development.
IGFBP2 protects against pulmonary fibrosis through inhibiting P21-mediated senescence
Authors: Chiahsuan Chin , Lee John , Ravichandran Ranjith , Fleming Timothy , Wheatcroft Stephen , Kearney Mark , Bremner Ross , Mohanakumar Thalachallour , Flint David J , Sureshbabu Angara
Published: January 2021

Accumulation of senescent cells contributes to age related diseases including idiopathic pulmonary fibrosis (IPF). Insulin-like growth factor binding proteins (IGFBPs) are evolutionarily conserved proteins that play a vital role in many biological processes. Overall, little is known about the functions of IGFBP2 in the epigenetic regulation of cellular senescence and pulmonary fibrosis. Here, we show thatIgfbp2expression was significantly downregulated at both mRNA and protein levels in a low-dose bleomycin-induced pulmonary fibrosis model of aged mice. Using the reduced representation of bisulfite sequencing technique, we demonstratedIgfbp2downregulation is attributed to DNA methylation of CpG islands in fibrotic lungs of aged mice. Furthermore,Igfbp2siRNA knockdown increased both P53 and P21 protein levels in mouse lung epithelial cells exposed to hypoxia treatment. Lentiviral mediated expression ofIgfb2decreased P21 protein levels and significantly reduced beta galactosidase activity in mouse lung epithelial cells challenged with a senescent drug (atazanavir) and hypoxia treatments. Using the RT2 Profiler PCR Array, we found that P21, PAI-1, IRF-5 and IRF-7, important regulators of senescence pathway, were significantly downregulated specifically in type-II alveolar epithelial cells (AECs) of aged human-Igfbp2transgenic mice after bleomycin challenge. Finally, transgenic expression of human-Igfbp2in type-II AECs from aged bleomycin challenged mice significantly decreased senescent associated secretory phenotype factors and also reduced extracellular matrix markers compared to aged wild-type mice challenged with bleomycin injury. Collectively, these findings reveal that epigenetic repression ofIgfbp2promotes pulmonary fibrosis and that restoring IGFBP2 in fibrotic lungs could prove effective in IPF treatment.
Genetically Engineered Mice for Combinatorial Cardiovascular Optobiology
Authors: Lee Frank K. , Lee Jane C. , Shui Bo , Reining Shaun , Jibilian Megan , Small David M. , Jones Jason S. , Allan-Rahill Nathaniel H. , Lamont Michael R.E. , Rizzo Megan A. , Tajada Sendoa , Navedo Manuel F. , Santana Luis Fernando , Nishimura Nozomi , Kotlikoff Michael. I.
Published: January 2021

Optogenetic effectors and sensors provide a novel real-time window into complex physiological processes, enabling determination of molecular signaling processes within functioning cellular networks. However, the combination of these optical tools in mice is made practical by construction of genetic lines that are optically compatible and genetically tractable. We present a new toolbox of 21 mouse lines with lineage -specific expression of optogenetic effectors and sensors for direct biallelic combination, avoiding the multiallelic requirement of Cre recombinase -mediated DNA recombination, focusing on models relevant for cardiovascular biology. Optogenetic effectors (11 lines) or Ca2+sensors (10 lines) were selectively expressed in cardiac pacemaker cells, cardiomyocytes, vascular endothelial and smooth muscle cells, alveolar epithelial cells, lymphocytes, glia, and other cell types. Optogenetic effector and sensor function was demonstrated in numerous tissues. Arterial/arteriolar tone was modulated by optical activation of the second messengers InsP3(optoα1AR) and cAMP (optoß2AR), or Ca2+- permeant membrane channels (CatCh2) in smooth muscle (Acta2) and endothelium (Cdh5). Cardiac activation was separately controlled through activation of nodal/conducting cells or cardiac myocytes. We demonstrate combined effector and sensor function in biallelic mouse crosses: optical cardiac pacing and simultaneous cardiomyocyte Ca2+imaging in HCN4BAC-CatCh2/αMHC-GCaMP8 crosses. These experiments highlight the potential of these mice to explore cellular signalingin vivo, in complex tissue networks.
Poly (I:C)-induced maternal immune activation modifies ventral hippocampal regulation of stress reactivity: prevention by environmental enrichment
Authors: Zhao Xin , Mohammed Ruqayah , Tran Hieu , Erickson Mary , Kentner Amanda C.
Published: January 2021

Environmental enrichment (EE) has been successfully implemented in human rehabilitation settings. However, the mechanisms underlying its success are not understood. Incorporating components of EE protocols into our animal models allows for the exploration of these mechanisms and their role in mitigation. Using a mouse model of maternal immune activation (MIA), the present study explored disruptions in social behavior and associated hypothalamic pituitary adrenal (HPA) axis functioning, and whether a supportive environment could prevent these effects. We show that prenatal immune activation of toll-like receptor 3, by the viral mimetic polyinosinic-polycytidylic acid (poly(I:C)), led to disrupted maternal care in that dams built poorer quality nests, an effect corrected by EE housing. Standard housed male and female MIA mice engaged in higher rates of repetitive rearing and had lower levels of social interaction, alongside sex-specific expression of several ventral hippocampal neural stress markers. Moreover, MIA males had delayed recovery of plasma corticosterone in response to a novel social encounter. Enrichment housing, likely mediated by improved maternal care, protected against these MIA-induced effects. We also evaluatedc-Fosimmunoreactivity associated with the novel social experience and found MIA to decrease neural activation in the dentate gyrus. Activation in the hypothalamus was blunted in EE housed animals, suggesting that the putative circuits modulating social behaviors may be different between standard and complex housing environments. These data demonstrate that augmentation of the environment supports parental care and offspring safety/security, which can offset effects of early health adversity by buffering HPA axis dysregulation. Our findings provide further evidence for the viability of EE interventions in maternal and pediatric settings.

Highlights

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Environmental enrichment (EE) protocols are used clinically to promote rehabilitation

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Use of EE in animal models may identify mechanisms underlying clinical successes

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Maternal immune activation (MIA) decreased social engagement; this effect was blocked by EE

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MIA reducedc-Fosactivation in the dentate gyrus, while EE reduced activation in the hypothalamus, in response to social stimuli

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EE inhibited MIA-induced HPA dysregulation in ventral hippocampus
Extracellular vesicles regulate yeast growth, biofilm formation, and yeast-to-hypha differentiation inCandida albicans
Authors: Honorato Leandro , Demetrio Joana Feital , Ellis Cameron C. , Piffer Alicia , Pereira Yan , Frases Susana , de Sousa Araújo Glauber Ribeiro , Pontes Bruno , Mendes Maria Tays , Pereira Marcos Dias , Guimarães Allan J. , da Silva Natalia Martins , Vargas Gabriele , Joffe Luna , Poeta Maurizio Del , Nosanchuk Joshua D. , Zamith Daniel , dos Reis Flavia Coelho Garcia , Rodrigues Marcio L. , de Toledo Martins Sharon , Alves Lysangela Ronalte , Almeida Igor C. , Nimrichter Leonardo
Published: January 2021

The ability to undergo morphological changes during adaptation to distinct environments is exploited byCandida albicansand has a direct impact on virulence. In this study, we investigated the influence of fungal extracellular vesicles (EVs) during yeast growth, biofilm formation, and morphogenesis inC. albicans. Addition ofC. albicansEVs (CaEVs) to the culture medium positively affected yeast growth. Using crystal violet staining and scanning electron microscopy (SEM), we demonstrated thatCaEVs inhibited biofilm formation byC. albicans in vitro. By time-lapse microscopy and SEM, we showed thatCaEV-treatment stops filamentation promoting pseudohyphae formation with multiple sites for yeast budding. The ability ofCaEVs to regulate dimorphism was further compared to EVs isolated from differentC. albicansstrains,Saccharomyces cerevisiae, andHistoplasma capsulatum.CaEVs from distinct strains robustly inhibited yeast-to-hyphae differentiation with morphological changes occurring in less than 4 hours. A minor inhibitory effect was promoted by EVs fromS. cerevisiaeandH. capsulatumonly after 24 hours of incubation. The inhibitory effect ofCaEVs was promoted by a combination of lipid compounds identified by gas chromatography-tandem mass spectrometry analysis as sesquiterpenes, diterpenes, and fatty acids. Remarkably,CaEVs were also able to reverse filamentation, transforming hyphal growth to yeast forms. Transcriptomic analysis demonstrated that treatment withCaEVs modified the expression of more than 300 genes. The most effectively upregulated pathways were related to DNA metabolism. The downregulated genes were mostly associated with extracellular and adhesion proteins. Finally, yeast cells treated withCaEVs for 24 hours lost their agar invasive ability and were avirulent when inoculated inGalleria mellonellalarvae. In summary, our results indicate that fungal EVs can profoundly modifyC. albicansgrowth and regulate yeast-to-hypha differentiation inhibiting biofilm formation and virulence.
A single cell atlas reveals unanticipated cell type complexity inDrosophilaovaries
Authors: Slaidina Maija , Gupta Selena , Banisch Torsten , Lehmann Ruth
Published: January 2021

Organ function relies on the spatial organization and functional coordination of numerous cell types. TheDrosophilaovary is a widely used model system to study the cellular activities underlying organ function, including stem cell regulation, cell signaling and epithelial morphogenesis. However, the relative paucity of cell type specific reagents hinders investigation of molecular functions at the appropriate cellular resolution.

Here, we used single cell RNA sequencing to characterize all cell types of the stem cell compartment and early follicles of theDrosophilaovary. We computed transcriptional signatures and identified specific markers for nine states of germ cell differentiation, and 23 somatic cell types and subtypes. We uncovered an unanticipated diversity of escort cells, the somatic cells that directly interact with differentiating germline cysts. Three escort cell subtypes reside in discrete anatomical positions, and express distinct sets of secreted and transmembrane proteins, suggesting that diverse micro-environments support the progressive differentiation of germ cells. Finally, we identified 17 follicle cell subtypes, and characterized their transcriptional profiles. Altogether, we provide a comprehensive resource of gene expression, cell type specific markers, spatial coordinates and functional predictions for 34 ovarian cell types and subtypes.
PIKfyve inhibition blocks endolysosomal escape of α-synuclein fibrils and spread of α-synuclein aggregation
Authors: See Stephanie K. , Chen Merissa , Bax Sophie , Tian Ruilin , Woerman Amanda , Tse Eric , Johnson Isabel E. , Nowotny Carlos , Muñoz Elise N. , Sengstack Janine , Southworth Daniel R. , Gestwicki Jason E. , Leonetti Manuel D. , Kampmann Martin
Published: January 2021

The inter-cellular prion-like propagation of α-synuclein aggregation is emerging as an important mechanism driving the progression of neurodegenerative diseases including Parkinson’s disease and multiple system atrophy (MSA). To discover therapeutic strategies reducing the spread of α-synuclein aggregation, we performed a genome-wide CRISPR interference screen in a human cell-based model. We discovered that inhibiting PIKfyve dramatically reduced α-synuclein aggregation induced with both recombinant α-synuclein fibrils and fibrils isolated from MSA patient brain. While PIKfyve inhibition did not affect fibril uptake or α-synuclein clearance or secretion, it reduced α-synuclein trafficking from the early endosome to the lysosome, thereby limiting fibril escape from the lysosome and reducing the amount of fibrils that reach cytosolic α-synuclein to induce aggregation. These findings point to the endolysosomal transport of fibrils as a critical step in the propagation of α-synuclein aggregation and a potential therapeutic target.
Recovery of consolidation after sleep following experimental stroke – interaction of slow waves, spindles and GABA
Authors: Kim Jaekyung , Guo Ling , Hishinuma April , Lemke Stefan , Ramanathan Dhakshin S. , Won Seok-Joon , Ganguly Karunesh
Published: January 2021

Sleep is known to be important for promoting recovery after brain injuries such as stroke. Yet, it remains unclear how such injuries affect neural processing during sleep and how to precisely enhance sleep-dependent memory processing during recovery. Using an experimental model of focal cortical stroke in rats along with long-term electrophysiological monitoring of neural firing and sleep microarchitecture, here we show that sleep-dependent neural processing is altered after stroke induction. Specifically, we found that the precise coupling of spindles to global slow- oscillations (SO), a phenomenon that is known to be important for memory consolidation, appeared to be disrupted by a pathological increase in “isolated” local delta waves. The transition from this pathological to a more physiological sleep state – with both a reduction in isolated delta waves and increased spindle coupling to SO – was associated with sustained performance gains after task training during recovery. Interestingly, post-injury sleep processing could be pushed towards a more physiological state via a pharmacological reduction of tonic GABA. Together, our results suggest that sleep processing after cortical brain injuries may be impaired due to an increase in local delta waves and that restoration of physiological processing is important for recovery of task performance.
Graph neural network based heterogeneous propagation scheme for classifying alzheimer’s disease
Authors: Byun Jiyoung , Jeong Yong
Published: January 2021

Deep learning frameworks for disease classification using neuroimaging and non-imaging information require the capability of capturing individual features as well as associative information among subjects. Graphs represent the interactions among nodes, which contain the individual features, through the edges in order to incorporate the inter-relatedness among heterogeneous data. Previous graph-based approaches for disease classification have focused on the similarities among subjects by establishing customized functions or solely based on imaging features. The purpose of this paper is to propose a novel graph-based deep learning architecture for classifying Alzheimer’s disease (AD) by combining the resting-state functional magnetic resonance imaging and demographic measures without defining any study-specific function. We used the neuroimaging data from the ADNI and OASIS databases to test the robustness of our proposed model. We combined imaging-based and non-imaging information of individuals by categorizing them into distinctive nodes to construct asubject–demographic bipartite graph. The approximate personalized propagation of neural predictions, a recently developed graph neural network model, was used to classify the AD continuum from cognitively unimpaired individuals. The results showed that our model successfully captures the heterogeneous relations among subjects and improves the quality of classification when compared with other classical and deep learning models, thus outperforming the other models.
Presynaptic NMDA receptors facilitate short-term plasticity and BDNF release at hippocampal mossy fiber synapses
Authors: Lituma Pablo J. , Kwon Hyung-Bae , Alviña Karina , Lujan Rafael , Castillo Pablo E.
Published: January 2021

Neurotransmitter release is a highly controlled process by which synapses can critically regulate information transfer within neural circuits. While presynaptic receptors –typically activated by neurotransmitters and modulated by neuromodulators– provide a powerful way of fine-tuning synaptic function, their contribution to activity-dependent changes in transmitter release remains poorly understood. Here, we report that presynaptic NMDA receptors (preNMDARs) at mossy fiber boutons in the rodent hippocampus can be activated by physiologically relevant patterns of activity and selectively enhance short-term synaptic plasticity at mossy fiber inputs onto CA3 pyramidal cells and mossy cells, but not onto inhibitory interneurons. Moreover, preNMDARs facilitate brain-derived neurotrophic factor (BDNF) release and contribute to presynaptic calcium rise. Taken together, our results indicate that by increasing presynaptic calcium, preNMDARs fine tune mossy fiber neurotransmission and can control information transfer during dentate granule cell burst activity that normally occurin vivo.