bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of Obesity and Cardiometabolic Status by Integrase Inhibitor Use in REPRIEVE: A Propensity-Weighted Analysis of a Multinational Primary Cardiovascular Prevention Cohort of People With Human Immunodeficiency Virus
Authors: Kileel Emma M , Lo Janet , Malvestutto Carlos , Fitch Kathleen V , Zanni Markella V , Fichtenbaum Carl J , Overton Edgar T , Okeke Nwora Lance , Kumar Princy , Joao Esau , Aberg Judith A , Martinez Esteban , Currier Judith S , Douglas Pamela S , Ribaudo Heather J , Grinspoon Steven K
Published: December 2021

Background

Emerging data demonstrate that the use of integrase inhibitor (INSTI)-based antiretroviral treatment (ART) is associated with increased weight, but the cardiometabolic health consequences of increased weight remains poorly understood.

Methods

This analysis examined INSTI use (>6 months) at entry among REPRIEVE participants enrolled in High Income and Latin America/Caribbean Global Burden of Disease regions. Primary analyses used linear and logistic regression; secondary analyses used quantile regression to examine differences across the full data distribution. Characteristics of those with and without INSTI use were balanced using inverse probability of treatment weighting.

Results

Among 4500 REPRIEVE participants, 1848 were on an INSTI-based regimen at entry for an average of 2.1 ± 1.8 years. Integrase inhibitor use (vs no INSTI use) was associated with higher odds of obesity (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.4–1.9) and higher mean body mass index ([BMI] +1.5kg/m2; 95% CI, 1.0–1.9) and waist circumference (+3.6cm; 95% CI, 2.6–4.6). Differences in weight related to INSTI use were greater in the upper tails of the distribution (+3.1kg/m2 [95% CI, 1.9–4.4] at the 90th centile vs +0.7kg/m2 [95% CI, 0.2–1.2] at the 50th centile) and among women and nonwhite participants, with sex and race having an additive effect on BMI. Conversely, INSTI use was not associated with differences in glucose, low-density lipoprotein cholesterol, or higher odds of metabolic syndrome or hypertension.

Conclusions

Differences in weight and waist circumference associated with INSTI use are (1) not uniform across people with human immunodeficiency virus, (2) greatest among women and nonwhites, and (3) concentrated at the upper tails of weight distribution. These data identify at-risk subgroups for whom long-term cardiovascular disease outcomes should be carefully assessed.
Root electrotropism in Arabidopsis does not depend on auxin distribution but requires cytokinin biosynthesis
Authors: Salvalaio Maddalena , Oliver Nicholas , Tiknaz Deniz , Schwarze Maximillian , Kral Nicolas , Kim Soo-Jeong , Sena Giovanni
Published: December 2021

Efficient foraging by plant roots relies on the ability to sense multiple physical and chemical cues in soil and to reorient growth accordingly (tropism). Root tropisms range from sensing gravity (gravitropism), light (phototropism), water (hydrotropism), touch (thigmotropism), and more. Electrotropism, also known as galvanotropism, is the phenomenon of aligning growth with external electric fields and currents. Although root electrotropism has been observed in a few species since the end of the 19th century, its molecular and physical mechanisms remain elusive, limiting its comparison with the more well-defined sensing pathways in plants. Here, we provide a quantitative and molecular characterization of root electrotropism in the model system Arabidopsis (Arabidopsis thaliana), showing that it does not depend on an asymmetric distribution of the plant hormone auxin, but instead requires the biosynthesis of a second hormone, cytokinin. We also show that the dose–response kinetics of the early steps of root electrotropism follows a power law analogous to the one observed in some physiological reactions in animals. Future studies involving more extensive molecular and quantitative characterization of root electrotropism would represent a step toward a better understanding of signal integration in plants and would also serve as an independent outgroup for comparative analysis of electroreception in animals and fungi.
Sleep as a predictor of tDCS and language therapy outcomes
Authors: Herrmann Olivia , Ficek Bronte , Webster Kimberly T , Frangakis Constantine , Spira Adam P , Tsapkini Kyrana
Published: December 2021

Study Objectives

To determine whether sleep at baseline (before therapy) predicted improvements in language following either language therapy alone or coupled with transcranial direct current stimulation (tDCS) in individuals with primary progressive aphasia (PPA).

Methods

Twenty-three participants with PPA (mean age 68.13 ± 6.21) received written naming/spelling therapy coupled with either anodal tDCS over the left inferior frontal gyrus (IFG) or sham condition in a crossover, sham-controlled, double-blind design (ClinicalTrials.gov identifier: NCT02606422). The outcome measure was percent of letters spelled correctly for trained and untrained words retrieved in a naming/spelling task. Given its particular importance as a sleep parameter in older adults, we calculated sleep efficiency (total sleep time/time in bed x100) based on subjective responses on the Pittsburgh Sleep Quality Index (PSQI). We grouped individuals based on a median split: high versus low sleep efficiency.

Results

Participants with high sleep efficiency benefited more from written naming/spelling therapy than participants with low sleep efficiency in learning therapy materials (trained words). There was no effect of sleep efficiency in generalization of therapy materials to untrained words. Among participants with high sleep efficiency, those who received tDCS benefitted more from therapy than those who received sham condition. There was no additional benefit from tDCS in participants with low sleep efficiency.

Conclusion

Sleep efficiency modified the effects of language therapy and tDCS on language in participants with PPA. These results suggest sleep is a determinant of neuromodulation effects.

Clinical Trial: tDCS Intervention in Primary Progressive Aphasia https://clinicaltrials.gov/ct2/show/NCT02606422
Obesity during pregnancy
Authors: Holland Tamara
Published: December 2021

Effective and empathetic communication is key to successful weight management before, during, and after pregnancy.
Opioids and Public Health: The Prescription Opioid Ecosystem and Need for Improved Management
Authors: Kharasch Evan D. , Clark J. David , Adams Jerome M.
Published: December 2021

While U.S. opioid prescribing has decreased 38% in the past decade, opioid deaths have increased 300%. This opioid paradox is poorly recognized. Current approaches to opioid management are not working, and new approaches are needed. This article reviews the outcomes and shortcomings of recent U.S. opioid policies and strategies that focus primarily or exclusively on reducing or eliminating opioid prescribing. It introduces concepts of a prescription opioid ecosystem and opioid pool, and it discusses how the pool can be influenced by supply-side, demand-side, and opioid returns factors. It illuminates pressing policy needs for an opioid ecosystem that enables proper opioid stewardship, identifies associated responsibilities, and emphasizes the necessity of making opioid returns as easy and common as opioid prescribing, in order to minimize the size of the opioid pool available for potential diversion, misuse, overdose, and death. Approaches are applicable to opioid prescribing in general, and to opioid prescribing after surgery.
The Utility of COMPASS-31 Questionnaire to Predict Autonomic Dysfunction in Patients With Cervical/Upper Thoracic Compressive Myelopathy
Authors: Takri Tanushree , Mathew Rosen Roy , Sivadasan Ajith , Raju Krishnaprabhu , Karuppusami Reka , Mariappan Ramamani
Published: December 2021

Background:

Patients with cervical/upper thoracic compressive myelopathy may have autonomic dysfunction. The composite autonomic severity score (CASS) is the gold standard test to detect autonomic dysfunction, and the self-rated composite autonomic system scale (COMPASS-31) questionnaire is a screening tool to diagnose autonomic dysfunction. This study compared the COMPASS-31 and modified CASS scores for the detection of autonomic dysfunction in patients with compressive myelopathy.

Methods:

Patients with cervical/upper thoracic compressive myelopathy scheduled for decompressive surgery completed a COMPASS-31 questionnaire and underwent autonomic function tests to calculate the modified CASS score before surgery.

Results:

Forty-two patients were included in the study; 19 (45.2%) had mild autonomic dysfunction, 5 (11.9%) had moderate autonomic dysfunction, and 18 (42.9%) had severe autonomic dysfunction. Median (interquartile range) of modified CASS and COMPASS-31 scores were 19 (6.33) and 3 (2.5), respectively. There was a positive correlation between modified CASS and COMPASS-31 scores (r=0.43; P=0.004). Receiver operating characteristic curve analysis confirmed that COMPASS-31 had fair accuracy for prediction of moderate to severe autonomic dysfunction (area under the curve, 0.74; 95% confidence interval, 0.64-0.82; P=0.009). A cut-off of 30 for total COMPASS-31 score had a sensitivity of 52.2% and specificity of 89.5% to detect moderate to severe autonomic dysfunction, with positive and negative predictive values of 85.7% and 60.7%, respectively.

Conclusion:

Patients with cervical/upper thoracic compressive myelopathy had varying degrees of autonomic dysfunction based on the modified CASS. There was a positive correlation between the modified CASS and COMPASS-31 questionnaire. A COMPASS-31 score of >30 30 could be utilized to predict moderate to severe autonomic dysfunction in patients with compressive myelopathy.
Advantages of a Dedicated Orthopaedic Trauma Operating Room for Diaphyseal Femur Fractures
Authors: Cloud Corinne , Fong Bronson , Bloise Christopher , Leonardi Claudia , Krause Peter C. , Lee Olivia C.
Published: December 2021

Objective:

To examine the impact of instituting a dedicated orthopaedic trauma operating room (DOTOR) at a Level I trauma center on diaphyseal femur fracture management.

Design:

Retrospective cohort study.

Setting:

Regional, university-based Level I trauma center.

Patients:

Trauma patients 18–65 years of age who presented between October 2016 and December 2018 (approximately 1 year before and after implementation of the DOTOR) and underwent surgery for diaphyseal femur fractures. One hundred twenty-eight patients met eligibility criteria for inclusion: 60 were treated before and 68 after implementation of the DOTOR.

Intervention:

Implementation of a DOTOR in October 2017.

Main Outcome Measures:

Percentage of external fixation versus intramedullary nailing, time from emergency department visit to definitive fixation, duration of surgery, and hospital length of stay.

Results:

The only significant difference in patient demographics between the before and after groups was mechanism of injury (P = 0.003). Percentage of external fixators as an initial procedure decreased from 15% to 2.9% (P = 0.024). Time to definitive fixation with intramedullary nail decreased from 1083 minutes to 659 minutes (P = 0.002). There was no significant change in median operative time of intramedullary nailing (P = 0.573). Although not statistically significant, hospital length of stay decreased from 7 days to 5.5 days after implementation (P = 0.158). Cost analysis revealed annual cost savings of more than $261,678 for diaphyseal femur fractures alone by implementing a DOTOR.

Conclusions:

For diaphyseal femur fractures, instituting a DOTOR at a Level I trauma center reduced the percentage of patients requiring a 2-stage fixation, reduced the time to definitive fixation, and yielded cost savings.

Level of Evidence:

Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Advances in measuring DNA methylation
Authors: Sun Ruixia , Zhu Ping
Published: December 2021

DNA methylation is one of the most important components of epigenetics, which plays essential roles in maintaining genome stability and regulating gene expression. In recent years, DNA methylation measuring methods have been continuously optimized. Combined with next generation sequencing technologies, these approaches have enabled the detection of genome-wide cytosine methylation at single-base resolution. In this paper, we review the development of 5-methylcytosine and its oxidized derivatives measuring methods, and recent advancement of single-cell epigenome sequencing technologies, offering more referable information for the selection and optimization of DNA methylation sequencing technologies and related research.
Validation of an MRI-based prostate cancer prebiopsy Gleason score predictive nomogram
Authors: Lee Adrianna Jiaying , Wnorowski Amelia , Ye Nancy , Xu Linhan , Naslund Michael , Wood Bradford J. , Merino Maria J. , Turkbey Baris , Choyke Peter L. , Pinto Peter A. , Siddiqui M. Minhaj
Published: December 2021

Background:

Gleason score grading is a cornerstone of risk stratification and management of patients with prostate cancer (PCa). In this work, we derive and validate a nomogram that uses prostate multiparametric magnetic resonance imaging (MP-MRI) and clinical patient characteristics to predict biopsy Gleason scores (bGS).

Materials and methods:

A predictive nomogram was derived from 143 men who underwent MP-MRI prior to any prostate biopsy and then validated on an independent cohort of 235 men from a different institution who underwent MP-MRI for PCa workup. Screen positive lesions were defined as lesions positive on T2W and DWI sequences on MP-MRI. Prostate specific antigen (PSA) density, number of screen positive lesions, and MRI suspicion were associated with PCa Gleason score on biopsy and were used to generate a predictive nomogram. The independent cohort was tested on the nomogram and the most likely bGS was noted.

Results:

The mean PSA in the validation cohort was 9.25ng/mL versus 6.8ng/mL in the original cohort (p = 0.001). The distribution of Gleason scores between the 2 cohorts were not significantly different (p = 0.7). In the original cohort of men, the most probable nomogram generated Gleason score agreed with actual pathologic bGS findings in 61% of the men. In the validation cohort, the most likely nomogram predicted bGS agreed with actual pathologic bGS 51% of the time. The nomogram correctly identified any PCa versus non-PCa 63% of the time and clinically significant (Gleason score ≥ 7) PCa 69% of the time. The negative predictive value for clinically significant PCa using this prebiopsy nomogram was 74% in the validation group.

Conclusions:

A preintervention nomogram based on PSA and MRI findings can help narrow down the likely pathologic finding on biopsy. Validation of the nomogram demonstrated a significant ability to correctly identify the most likely bGS. This feasibility study demonstrates the potential of a prebiopsy prediction of bGS and based on the high negative predictive value, identification of men who may not need biopsies, which could impact future risk stratification for PCa.
Serum apolipoprotein A1 rather than apolipoprotein B is associated with hypertension prevalence in Chinese people with coronary artery disease
Authors: Dong Hongli , Zhang Yaju , Hu Ping , Wang Jie , Lu Nan
Published: December 2021

Objective

Studies on the association of apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB) with hypertension (HTN) prevalence in patients with coronary artery disease (CAD) are limited. This cross-sectional study aimed to investigate this association in Chinese people in Wuhan, China.

Methods

Serum ApoA1 and ApoB levels were measured by immunoturbidimetry assay. Logistic regression analysis was used to estimate the associations of ApoA1 and ApoB level and ApoB/A1 ratio with HTN prevalence.

Results

We included 5192 individuals (3060 men, mean age 61 years; 4412 HTN cases) in this study. After adjusting for covariates, serum ApoA1 but not ApoB level or ApoB/A1 ratio was inversely associated with HTN prevalence. HTN prevalence was reduced with the fifth versus first quintile of ApoA1 level [odds ratio = 0.78 (95% confidence interval 0.62-0.98)]. In stratified analyses based on sex, the probability of HTN with the fifth versus first ApoA1 level was 0.71 (0.53-0.96) for men. The probability of HTN with the fifth versus first quintile of ApoB/A1 ratio was 1.54 (1.11-2.13) after adjustment. With quintiles 2–5 versus of ApoB level, the probability of HTN did not differ in both men and women. On path analyses, the association of ApoA1 level and ApoB/A1 ratio with HTN was mediated by BMI (β coefficients: –0.179 to 0.133).

Conclusion

In general, high serum ApoA1 level may be associated with a reduced probability of HTN prevalence in patients with CAD in China, and this association may be mediated by BMI.
Association Analysis Between HLA-DQA1 Loci and Neuromyelitis Optica Spectrum Disorder in a Han Chinese Population
Authors: Zhou Lili , He Zhiyong , Zhu Lanbing , Zhu Juan-juan , Zhu Jian-Hong , Pan Jialin
Published: December 2021

Background:

Genome-wide association studies for neuromyelitis optica spectrum disorder (NMOSD) have established an association between HLA-DQ alpha 1 (DQA1) and risk for NMOSD. Though ethnicity is generally considered a major influencing factor in genetic analyses, little is known regarding the association of HLA-DQA1 polymorphisms with NMOSD in the Han population, especially the single-nucleotide polymorphisms (SNPs) at HLA-DQA1.

Methods:

We genotyped SNP at loci rs28383224 in a case-control study consisting of 137 subjects (51 patients with NMOSD and 86 unrelated controls were recruited) of Han ethnicity. Logistic regression was used to test the association of SNP with NMOSD susceptibility, the sex and age were adjusted, odds ratios and 95% confidence intervals were estimated.

Results:

The rs28383224 polymorphism and susceptibility to NMOSD were not statistically associated (P>0.05) in the Han population in the current study. No significant difference was found in allelic frequencies or genotypic distributions among different subsets of NMOSD patients (P>0.05).

Conclusion:

In the current study, there is no evidence that polymorphism of rs28383224 in the HLA-DQA1 gene is associated with the risk of NMOSD in the Han Chinese population.
Pediatric Blunt Abdominal Trauma and Point-of-Care Ultrasound
Authors: Fornari Marci J. , Lawson Simone L.
Published: December 2021

Blunt abdominal trauma (BAT) accounts for most trauma in children. Although the focused assessment with sonography in trauma (FAST) is considered standard of care in the evaluation of adults with traumatic injuries, there is limited evidence to support its use as an isolated evaluation tool for intra-abdominal injury as a result of BAT in children. Although a positive FAST examination could obviate the need for a computed tomography scan before OR evaluation in a hemodynamically unstable patient, a negative FAST examination cannot exclude intra-abdominal injury as a result of BAT in isolation. In this article, we review the evaluation of BAT in children, describe the evaluation for free intraperitoneal fluid and pericardial fluid using the FAST examination, and discuss the limitations of the FAST examination in pediatric patients.
Regional Differences in School-Based Physical Therapy Practice for Students Who Made Progress on 2 Outcome Measures
Authors: Caldwell Michele , Effgen Susan , Tezanos Alejandro Villasante , Sylvester Lorraine , Jeffries Lynn M.
Published: December 2021

Purpose:

This study examined whether regional differences exist in the provision of school-based physical therapy services for students who achieved positive progress and explored relationships between student outcomes and school-based physical therapy.

Methods:

Physical therapists developed student goals using Goal Attainment Scaling (GAS) and administered the School Function Assessment (SFA). Therapists documented activities, interventions, and type of service delivery provided weekly. Students were assigned to regions for analysis.

Results:

Student GAS goal attainment and progress on the SFA did not vary significantly among regions. The dosage of school-based physical therapy services, interventions, and activities varied.

Conclusions:

There were regional differences that did not impact goal achievement. Further research is needed to identify the most efficient and effective interventions and dosage to support student outcomes.
Blunt Cerebrovascular Injury-Like Injury Observed in Patients With Craniofacial Self-Inflicted Gunshot Wounds
Authors: Yoon Joshua , Gebran Selim , Elegbede Adekunle , Day Samantha , Wasicek Philip , Liang Yuanyuan , Rasko Yvonne , Grant Michael P. , Nam Arthur J. , Bodanapally Uttam K. , Sliker Clint W. , Liang Fan
Published: December 2021

Background:

Although blunt cerebrovascular injury (BCVI) is recognized as a risk factor for trauma morbidity and mortality, little is described regarding similar cerebrovascular injury (CVI) in patients with penetrating wounds. The authors aim to characterize these injuries in the craniofacial self-inflicted gunshot wound (SIGSW) population.

Methods:

An institutional review board (IRB)-approved retrospective nstudy was conducted on patients presenting to the R Adams Cowley Shock Trauma Center with SIGSWs between 2007 and 2016. All CVIs were categorized by location, type, and associated neurologic deficits. Demographic data, patient characteristics, additional studies, and long-term outcomes were collected. A multivariate analysis determining independent predictors of CVI in the SIGSW population was performed.

Results:

Of the 73 patients with SIGSWs, 5 (6.8%) had CVIs separate from the bullet/cavitation tract (distant CVIs) and 9 had CVIs along the bullet/cavitation tract (in-tract CVIs). A total of 55.6% of in-tract and 40% of distant injuries were missed on initial radiology read. One distant CVI patient suffered a stroke during admission. The anterior to posterior gunshot wound trajectory was positively associated with distant CVIs when compared with no CVIs (P = 0.01). Vessel dissection was more prevalent in patients with distant CVIs, when compared against patients with in-tract CVIs (P = 0.02).

Conclusions:

Nearly 20% of craniofacial SIGSW patients have CVIs and 6.8% have BCVI-like injuries, which is 2-to-6-fold times higher than traditional BCVIs. Craniofacial SIGSWs serve as an independent screening criterion with comparable screening yields; the authors recommend radiographic screening for these patients with particular scrutiny for CVIs as they are frequently missed on initial radiographic interpretations.
Emerging Concepts of Tissue-resident Memory T Cells in Transplantation
Authors: Fu Jianing , Sykes Megan
Published: December 2021

In this review, we summarize and discuss recent advances in understanding the characteristics of tissue-resident memory T cells (TRMs) in the context of solid organ transplantation (SOT). We first introduce the traditionally understood noncirculating features of TRMs and the key phenotypic markers that define this population, then provide a detailed discussion of emerging concepts on the recirculation and plasticity of TRM in mice and humans. We comment on the potential heterogeneity of transient, temporary resident, and permanent resident T cells and potential interchangeable phenotypes between TRM and effector T cells in nonlymphoid tissues. We review the literature on the distribution of TRM in human nonlymphoid organs and association of clinical outcomes in different types of SOT, including intestine, lung, liver, kidney, and heart. We focus on both tissue-specific and organ-shared features of donor- and recipient-derived TRMs after transplantation whenever applicable. Studies with comprehensive sample collection, including longitudinal and cross-sectional controls, and applied advanced techniques such as multicolor flow cytometry to distinguish donor and recipient TRMs, bulk, and single-cell T-cell receptor sequencing to track clonotypes and define transcriptome profiles, and functional readouts to define alloreactivity and proinflammatory/anti-inflammatory activities are emphasized. We also discuss important findings on the tissue-resident features of regulatory αβ T cells and unconventional γδ T cells after transplantation. Understanding of TRM in SOT is a rapidly growing field that urges future studies to address unresolved questions regarding their heterogeneity, plasticity, longevity, alloreactivity, and roles in rejection and tolerance.
Disrupted functional connectivity between the nucleus accumbens and posterior cingulate cortex in autism spectrum disorder
Authors: Polk MaryScott , Ikuta Toshikazu
Published: December 2021

Objectives

Dysfunctions in the basal ganglia have been repeatedly found in autism spectrum disorder (ASD). The nucleus accumbens (NAcc) is known for its central role in social functions and also in its abnormality in ASD. In this study, whole-brain functional connectivity of the NAcc was examined to isolate brain regions that are differently connected to the NAcc in autism, using resting-state functional MRI (rs-fMRI) data.

Methods

In the initial dataset, 68 individuals with ASD (13.13 ± 2.41 years old) and 77 typically developing individuals (14.79 ± 3.57 years old) were compared.

Results

The precuneus cortex, lingual gyrus, thalamus, dorsal striatum, anterior cingulate cortex and posterior cingulate cortex showed weaker connectivity to the NAcc in the group with ASD. Among these regions, dysconnectivity of the posterior cingulate cortex (PCC) was replicated in the replication dataset, with 78 individuals with ASD and 105 without ASD.

Conclusions

This study suggests that the dysconnectivity between the NAcc and PCC may account for social dysfunctions in ASD.
Telomere length and telomerase activity of leukocytes as biomarkers of selective serotonin reuptake inhibitor responses in patients with major depressive disorder
Authors: da Silva Raiany S. , de Moraes Leopoldo S. , da Rocha Carlos A. M. , Ferreira-Fernandes Hygor , Yoshioka France K. N. , Rey Juan A. , Pinto Giovanny R. , Burbano Rommel R.
Published: December 2021

We analyze the leukocyte telomere length (LTL) and telomerase activity in patients with major depressive disorder (MDD) before and after treatment with selective serotonin reuptake inhibitors (SSRIs). Before treatment, there was a reduction in the LTLs and expression levels of the human telomerase reverse transcriptase (hTERT) in the patients with MDD compared with controls. However, after 24 weeks of treatment with SSRIs, there was a significant increase in the LTLs and the expression levels of hTERT, with values approaching those observed in the controls. We conclude that SSRI antidepressant therapy can directly influence the increased expression levels of hTERT in patients.
Acuticoccus mangrovi sp. nov., with an antibacterial property, isolated from mangrove sediment
Authors: Li Zhe , Hu Wenjin , Huang Shushi , Huang Yuanlin , Li Fei , Wang Qiaozhen , Tao Zhanhua , Pan Xinli
Published: December 2021

A Gram-stain-negative, aerobic, milky white bacterium, designated B2012T, was isolated from mangrove sediment collected at Beibu Gulf, South China Sea. Antimicrobial activity assay revealed that the isolate possesses the capability of producing antibacterial compounds. Strain B2012T shared the highest 16S rRNA gene sequence relatedness (96.9–95.5 %) with members of the genus

Acuticoccus

. The isolate and all known

Acuticoccus

species contain Q-10 as the main respiratory quinone and have the same polar lipid components (phosphatidylcholine, unidentified glycolipid, unidentified lipid, unidentified amino lipid and phosphatidylglycerol). However, genomic relatedness referred by values of average nucleotide identity, digital DNA–DNA hybridization, average amino acid identity and the percentage of conserved proteins between strain B2012T and other type strains of the genus

Acuticoccus

were below the proposed thresholds for species discrimination. The genome of strain B2012T was assembled into 65 scaffolds with an N50 size of 244239 bp, resulting in a 5.5 Mb genome size. Eight secondary metabolite biosynthetic gene clusters were detected in this genome, including three non-ribosomal peptide biosynthetic loci encoding yet unknown natural products. Strain B2012T displayed moderately halophilic and alkaliphilic properties, growing optimally at 2–3 % (w/v) NaCl concentration and at pH 8–9. The major cellular fatty acids (>10 %) were anteiso-C15 : 0, C16 : 0 dimethyl aldehyde (DMA) and C16 : 0. Combined data from phenotypic, genotypic and chemotaxonomic analyses suggested that strain B2012T represents a novel species of the genus

Acuticoccus

, for which the name Acuticoccus mangrovi sp. nov. is proposed. The type strain of the type species is B2012T (=MCCC 1K04418T=KCTC 72962T).
Genome reorganization during emergence of host-associated Mycobacterium abscessus
Authors: Bohr Lindsey L. , Youngblom Madison A. , Eldholm Vegard , Pepperell Caitlin S.
Published: December 2021

Mycobacterium abscessus

is a rapid growing, free-living species of bacterium that also causes lung infections in humans. Human infections are usually acquired from the environment; however, dominant circulating clones (DCCs) have emerged recently in both

M. abscessus

subsp.

massiliense

and subsp. abscessus that appear to be transmitted among humans and are now globally distributed. These recently emerged clones are potentially informative about the ecological and evolutionary mechanisms of pathogen emergence and host adaptation. The geographical distribution of DCCs has been reported, but the genomic processes underlying their transition from environmental bacterium to human pathogen are not well characterized. To address this knowledge gap, we delineated the structure of

M. abscessus

subspecies

abscessus

and massiliense using genomic data from 200 clinical isolates of

M. abscessus

from seven geographical regions. We identified differences in overall patterns of lateral gene transfer (LGT) and barriers to LGT between subspecies and between environmental and host-adapted bacteria. We further characterized genome reorganization that accompanied bacterial host adaptation, inferring selection pressures acting at both genic and intergenic loci. We found that both subspecies encode an expansive pangenome with many genes at rare frequencies. Recombination appears more frequent in

M. abscessus

subsp.

massiliense

than in subsp. abscessus, consistent with prior reports. We found evidence suggesting that phage are exchanged between subspecies, despite genetic barriers evident elsewhere throughout the genome. Patterns of LGT differed according to niche, with less LGT observed among host-adapted DCCs versus environmental bacteria. We also found evidence suggesting that DCCs are under distinct selection pressures at both genic and intergenic sites. Our results indicate that host adaptation of

M. abscessus

was accompanied by major changes in genome evolution, including shifts in the apparent frequency of LGT and impacts of selection. Differences were evident among the DCCs as well, which varied in the degree of gene content remodelling, suggesting they were placed differently along the evolutionary trajectory toward host adaptation. These results provide insight into the evolutionary forces that reshape bacterial genomes as they emerge into the pathogenic niche.
Microevidence for microdosing with psilocybin mushrooms: a double-blind placebo-controlled study of subjective effects, behavior, creativity, perception, cognition, and brain activity
Authors: Cavanna Federico , Muller Stephanie , de la Fuente Laura Alethia , Zamberlan Federico , Palmucci Matías , Janeckova Lucie , Kuchar Martin , Pallavicini Carla , Tagliazucchi Enzo
Published: December 2021

The use of low sub-hallucinogenic doses of psychedelics (“microdosing”) has gained popularity in recent years. Although anecdotal reports claim multiple benefits associated with this practice, the lack of placebo-controlled studies limits our knowledge of microdosing and its effects. Moreover, research conducted in laboratory settings might fail to capture the motivation of individuals engaged in microdosing protocols. We recruited 34 individuals planning to microdose with psilocybin mushrooms (Psilocybe cubensis), one of the materials most frequently used for this purpose. Following a double-blind placebo-controlled design, we investigated the effects of 0.5 g dried mushrooms on subjective experience, behavior, creativity, perception, cognition, and brain activity. The reported acute effects were significantly more intense for the active dose compared to the placebo, which could be explained by unblinding. For the other measurements, we observed either null effects or a trend towards cognitive impairment and, in the case of EEG, towards reduced theta band spectral power. Our findings support the possibility that expectation effects underlie at least some of the anecdotal benefits attributed to microdosing with psilocybin mushrooms.
The Reputational Dividends of Collaborating with a Highly Reputable Agency: The Case of the FDA and Its Domestic Partner Agencies
Authors: Maor Moshe , Sulitzeanu-Kenan Raanan , Balmas Meital
Published: December 2021

What, if any, dividends do agencies reap from collaboration with a highly reputable agency, such as the FDA? Utilizing a dataset covering 30 U.S. federal agencies over a period of 34 years (1980–2013), we estimate the short and long-term reputational effects of interagency collaboration. Collaboration is measured by the number of memorandums of understanding (MOUs) in effect between each agency and the FDA, while agency reputation is assessed using an automated measure of media-coverage valence (positive/negative tone) for each agency-year. To account for potential reverse and reciprocal causality, we utilize cross-lagged fixed-effects models. We find evidence of moderate rises in reputation due to increased collaboration with the FDA. These effects persist significantly for two years, before decaying to null after four years. Employing similar analyses, we furthermore estimate reversed causality – of reputation on the level of consequent collaboration – finding no evidence of such effects.

Research Support

Moshe Maor and Raanan Sulitzeanu-Kenan gratefully acknowledge financial support from the Israel Science Foundation under grant 1002/11.
The Petasites hybridus CO2-extract (Ze 339) blocks SARS-CoV-2 replication in vitro
Authors: Urda Lorena , Kreuter Matthias Heinrich , Drewe Jürgen , Boonen Georg , Butterweck Veronika , Klimkait Thomas
Published: December 2021

The coronavirus disease 2019 (COVID-19), caused by a novel coronavirus (SARS-CoV-2), has spread worldwide, affecting over 250 million people and resulting in over five million deaths. Antivirals that are effective are still limited. The antiviral activities of the Petasites hybdridus CO2-extract Ze 339 were previously reported. Thus, to assess the anti-SARS-CoV-2 activity of Ze 339 as well as isopetasin and neopetasin as major active compounds, a CPE- and plaque reduction assay in Vero E6 cells was used for viral output. Antiviral effects were tested using the original virus (Wuhan) and the Delta variant of SARS-CoV-2. The antiviral drug remdesivir was used as control. Pre-treatment with Ze 339 in SARS-CoV-2 infected Vero E6 cells with either virus variant significantly inhibited virus replication with IC50 values of 0.10 and 0.40 μg/mL, repectively. The IC50 values obtained for isopetasin ranged between 0.37-0.88 μM for both virus variants, that of remdesivir between 1.53-2.37 μM. In conclusion, Ze 339 as well as the petasins potently inhibited SARS-Cov-2 replication in vitro of the Wuhan and Delta variants. Since time is of essence in finding effective treatments, clinical studies will have to demonstrate if Ze339 can become a therapeutic option to treat SARS-CoV-2 infections.
Modeling the trajectory of SARS-CoV-2 spike protein evolution in continuous latent space using a neural network and Gaussian process
Authors: King Samuel , Chen Xinyi E. , Ng Sarah W. S. , Rostin Kimia , Roberts Tylo , Hahn Samuel V. , Schwab Janella C. , Sekhon Parneet , Kagieva Madina , Reilly Taylor , Qi Ruo Chen , Salman Paarsa , Hong Ryan J. , Ma Eric J. , Hallam Steven J.
Published: December 2021

Viral vaccines can lose their efficacy as the genomes of targeted viruses rapidly evolve, resulting in new variants that may evade vaccine-induced immunity. This process is apparent in the emergence of new SARS-CoV-2 variants which have the potential to undermine vaccination efforts and cause further outbreaks. Predictive vaccinology points to a future of pandemic preparedness in which vaccines can be developed preemptively based in part on predictive models of viral evolution. Thus, modeling the trajectory of SARS-CoV-2 spike protein evolution could have value for mRNA vaccine development. Traditionally, in silico sequence evolution has been modeled discretely, while there has been limited investigation into continuous models. Here we present the Viral Predictor for mRNA Evolution (VPRE), an open-source software tool which learns from mutational patterns in viral proteins and models their most statistically likely evolutionary trajectories. We trained a variational autoencoder with real-time and simulated SARS-CoV-2 genome data from Australia to encode discrete spike protein sequences into continuous numerical variables. To simulate evolution along a phylogenetic path, we trained a Gaussian process model with the numerical variables to project spike protein evolution up to five months in advance. Our predictions mapped primarily to a sequence that differed by a single amino acid from the most reported spike protein in Australia within the prediction timeframe, indicating the utility of deep learning and continuous latent spaces for modeling viral protein evolution. VPRE can be readily adapted to investigate and predict the evolution of viruses other than SARS-CoV-2 in temporal, geographic, and lineage-specific pathways.
An antibody-escape calculator for mutations to the SARS-CoV-2 receptor-binding domain
Authors: Greaney Allison J. , Starr Tyler N. , Bloom Jesse D.
Published: December 2021

A key goal of SARS-CoV-2 surveillance is to rapidly identify viral variants with mutations that reduce neutralization by polyclonal antibodies elicited by vaccination or infection. Unfortunately, direct experimental characterization of new viral variants lags their sequence-based identification. Here we help address this challenge by aggregating deep mutational scanning data into an “escape calculator” that estimates the antigenic effects of arbitrary combinations of mutations to the virus’s spike receptor-binding domain (RBD). The calculator can be used to intuitively visualize how mutations impact polyclonal antibody recognition, and score the expected antigenic effect of combinations of mutations. These scores correlate with neutralization assays performed on SARS-CoV-2 variants, and emphasize the ominous antigenic properties of the recently described Omicron variant. An interactive version of the calculator is at https://jbloomlab.github.io/SARS2_RBD_Ab_escape_maps/escape-calc/, and we provide a Python module for batch processing.
Low-affinity CAR T cells exhibit reduced trogocytosis, preventing fratricide and antigen-negative tumor escape while preserving anti-tumor activity
Authors: Olson Michael L. , Vander Mause Erica R. , Radhakrishnan Sabarinath V. , Brody Joshua D. , Rapoport Aaron P. , Welm Alana L. , Atanackovic Djordje , Luetkens Tim
Published: December 2021

Chimeric antigen receptor (CAR) T cells using the high-affinity CD19 binding domain FMC63 are an effective treatment for patients with relapsed and aggressive B cell lymphoma. However, antigen loss and poor CAR T cell persistence remain common causes for relapse in these patients. Using primary patient samples, we now show that FMC63-based CAR T cells confer rapid antigen loss in all major tumor types currently approved for treatment with CD19 CAR T cells via trogocytosis, the stripping of antigen from tumor cells by CAR T cells. We show that CAR T cell-mediated trogocytosis can be dramatically reduced across a wide range of B cell malignancies by replacing FMC63 with a low affinity CD19 antibody. This reduction in trogocytosis does not alter the direct anti-tumor activity of CD19 CAR T cells but prevents the emergence of antigen-negative tumor cells and significantly increases CAR T cell viability by reducing fratricide of CD19 CAR T cells following trogocytosis.

TEASER

A reduction in CAR affinity does not affect tumor killing but prolongs T cell persistence and prevents antigen-negative tumor escape.
Control of nuclear size by osmotic forces in Schizosaccharomyces pombe
Authors: Lemière Joёl , Real-Calderon Paula , Holt Liam J. , Fai Thomas G. , Chang Fred
Published: December 2021

The size of the nucleus scales robustly with cell size so that the nuclear-to-cell volume ratio (N/C ratio) is maintained during cell growth in many cell types. The mechanism responsible for this scaling remains mysterious. Previous studies have established that the N/C ratio is not determined by DNA amount but is instead influenced by factors such as nuclear envelope mechanics and nuclear transport. Here, we developed a quantitative model for nuclear size control based upon colloid osmotic pressure and tested key predictions in the fission yeast Schizosaccharomyces pombe. This model posits that the N/C ratio is determined by the numbers of macromolecules in the nucleoplasm and cytoplasm. Osmotic shift experiments showed that the fission yeast nucleus behaves as an ideal osmometer whose volume is primarily dictated by osmotic forces. Inhibition of nuclear export caused accumulation of macromolecules and an increase in crowding in the nucleoplasm, leading to nuclear swelling. We further demonstrated that the N/C ratio is maintained by a homeostasis mechanism based upon synthesis of macromolecules during growth. These studies demonstrate the functions of colloid osmotic pressure in intracellular organization and size control.
“A novel paradigm for optimal mass feature peak picking in large scale LC-MS datasets using the ‘isopair’: isoLock, autoCredential and anovAlign”
Authors: Hubbard Allen , Connelly Louis , Kambhampati Shrikaar , Evans Brad , Baxter Ivan
Published: December 2021

Untargeted metabolomics enables direct quantification of metabolites without apriori knowledge of their identity. Liquid chromatography mass spectrometry (LC-MS), a popular method to implement untargeted metabolomics, identifies metabolites via combined mass/charge (m/z) and retention time as mass features. Improvements in the sensitivity of mass spectrometers has increased the complexity of data produced, leading to computational obstacles. One outstanding challenge is calling metabolite mass feature peaks rapidly and accurately in large LC-MS datasets (dozens to thousands of samples) in the presence of measurement and other noise. While existing algorithms are useful, they have limitations that become pronounced at scale and lead to false positive metabolite predictions as well as signal dropouts. To overcome some of these shortcomings, biochemists have developed hybrid computational and carbon labeling techniques, such as credentialing. Credentialing can validate metabolite signals, but is laborious and its applicability is limited. We have developed a suite of three computational tools to overcome the challenges of unreliable algorithms and inefficient validation protocols: isolock, autoCredential and anovAlign. Isolock uses isopairs, or metabolite-istopologue pairs, to calculate and correct for mass drift noise across LC-MS runs. autoCredential leverages statistical features of LC-MS data to amplify naturally present 13C isotopologues and validate metabolites through isopairs. This obviates the need to artificially introduce carbon labeling. anovAlign, an anova-derived algorithm, is used to align retention time windows across samples to accurately delineate retention time windows for mass features. Using a large published clinical dataset as well as a plant dataset with biological replicates across time, genotype and treatment, we demonstrate that this suite of tools is more sensitive and reproducible than both an open source metabolomics pipelines, XCMS, and the commercial software progenesis QI. This software suite opens a new era for enhanced accuracy and increased throughput for untargeted metabolomics.
Heterozygous transcriptional signatures unmask variable premature termination codon (PTC) burden alongside pathway-specific adaptations in blood outgrowth endothelial cells from patients with nonsense DNA variants causing hereditary hemorrhagic telangiectasia
Authors: Bernabeu-Herrero Maria E , Patel Dilip , Bielowka Adrianna , Guerrero Patricia Chaves , Marciniak Stefan J , Noseda Michela , Aldred Micheala A. , Shovlin Claire L
Published: December 2021

Frameshift and nonsense DNA variants represent the commonest causes of monogenic inherited diseases. They usually generate premature termination codon (PTC)-containing RNA transcripts that produce truncated proteins in recombinant systems, but endogenously are subject to nonsense mediated decay. To examine native consequences of these variants, we derived cells from pre-genotyped patients. Blood outgrowth endothelial cells (BOECs) were established from individuals with hereditary hemorrhagic telangiectasia (HHT) due to a heterozygous nonsense variant inACVRL1,ENGorSMAD4that each encode an endothelial cell-expressed protein mediating bone morphogenetic protein (BMP)/ transforming growth factor (TGF)-β signalling. RNA sequencing alignments to PTC alleles varied from 8-23% of expected, and differed between same-donor replicates. Differential gene expression analyses were validated by single cell qRT-PCR, and identification of changes in wider, disease-specific BMP/TGF-β pathway components. However, the most differentially expressed genes clustered to disease-independent terms for post translational protein modification (isopeptide bond; ubiquitin-like conjugation). They were the only terms meeting Benjamini significance after clustering Bonferroni-ranked, differentially expressed genes from the 5,013 meeting 10% intraassay coefficients of variation, and significance was robust to normalisation methods. Optimised pulse chase experiments supported perturbed wildtype protein maturation, but no PTC-truncated protein was identified. Unexpectedly, BOEC cultures with highest PTC persistence were discriminated in unsupervised hierarchical clustering of low GINI coefficient ‘invariant’ housekeeper genes, and patterns were compatible with higher cellular stress. The findings support a model whereby PTCs are more of a burden in stressed cells, and lead us to conclude that overlooked and varying PTC burdens contribute to biological variability.
Traditional martial arts and shooting training have different effects on auditory fine structure processing ability——Evidence from behavioral tests and fMRI
Authors: Ding Yu , Zhang Keying , Cao Chunmei
Published: December 2021

Explore the influence of traditional martial arts and shooting training on the ability of auditory temporal fine structure (TFS) processing. Twenty-five college students participated in the experiment, including 8 traditional martial arts practitioners, 8 high-level shooting athletes, and 9 control groups without any regular exercise habits. The BIC (break in interaural correlation) delay threshold and TFS1 test were used to evaluate the temporary storage capacity and sensitivity of TFS, respectively, and a fMRI test was performed after the test. The results found that the traditional martial arts group had stronger TFS sensitivity, while the shooting group had stronger TFS retention ability, and the performance of the behavioral test of the shooting group is related to the fALFF value of the brain area of interest. Traditional martial arts and shooting training have improved the ability of auditory information processing from different angles, diversified exercise habits will lead to the development of diversity in brain structure and function.