bluuebunny/crossref_metadata_2025 huggingface dataset:
Rectal inflammatory myofibroblastic tumor
Authors: Oh Hyung-Hoon , Joo Young-Eun
Published: August 2021

Rationale:

Rectal inflammatory myofibroblastic tumor (IMT) is an extremely rare mesenchymal tumor characterized by a mixture of spindle-shaped myofibroblasts or fibroblasts and inflammatory infiltration of lymphocytes and plasma cells. To date, only 8 cases of rectal IMT have been reported. Herein, we report an additional case of rectal IMT in a 28-year-old woman.

Patient concerns:

A 28-year-old woman presented with abdominal pain and hematochezia.

Diagnoses:

Colonoscopy showed a 3.0-cm subepithelial tumor with central ulceration, covered by white exudate in the rectum. Rectal magnetic resonance imaging revealed a 4.0 × 3.0-cm-sized well-defined subepithelial tumor in the right wall of the rectum, with suspicious right perirectal fat infiltration.

Interventions:

Laparoscopic anterior resection was performed. Microscopic examination of the surgical specimen revealed bland-looking spindle cells intermingled with lymphoplasma cells. Immunohistochemistry and fluorescence in situ hybridization showed anaplastic lymphoma kinase positivity and anaplastic lymphoma kinase positivity rearrangement. Rectal IMT was confirmed based on histological, immunohistochemical, and fluorescence in situ hybridization findings. The patient was doing well without evidence of tumor recurrence 1 year after the surgery.

Lessons:

Rectal IMT, despite its rarity, should be considered in the differential diagnosis of rectal cancer. Second, an accurate histopathologic diagnosis and complete surgical resection can be the most important approaches to offer a chance for the cure of rectal IMT.
Complications after native kidney biopsy: definitive data
Authors: Halimi Jean-Michel
Published: August 2021

Purpose of review

To assess the risk of complications associated with native kidney biopsies. This review will highlight recent advances on the risk factors for major bleeding and risk management in patients with native kidney biopsy.

Recent findings

Recent studies provided new important data regarding the individualization of the risk of bleeding after kidney biopsy. A new bleeding risk score was proposed as a risk stratification tool, useful for shared decision making and procedure choice.

The risk of complications is low (<1%) in most patients but varies widely. Risk factors include Charlson index, frailty index, female gender, dyslipidemia, anemia, thrombocytopenia, cancer, abnormal kidney function, glomerular disease, autoimmune disease, vasculitis, hematologic disease, and thrombotic microangiopathy. A new bleeding score can help physicians and patients to assess the risk of bleeding enabling informed consent, and decide to perform it or not, and to prefer transjugular vs percutaneous route.
Current management of skull base osteomyelitis
Authors: Auinger Alice B. , Arnoldner Christoph
Published: August 2021

Purpose of review

Skull base osteomyelitis (SBO) is a life-threatening condition. Due to an aging and increasingly multimorbid population, clinicians are more often challenged with this disease. Yet, there is no consensus on the optimal diagnostic and follow-up management. This review should aid clinicians in decision-making for their patients.

Recent findings

Treatment-resistant otalgia or headache is suspicious of SBO. Pseudomonas aeruginosa remains the most common pathogen but clinicians are challenged with increasing rates of sterile or fungal cultures due to previously applied antibiotics/steroids. No single imaging modality is able to detect the full extent of the disease. Whereas functional nuclear imaging with gallium-67 or methylene diphosphonate-technetium-99m was once advocated, its actual benefit is questionable. Newer modalities such as fluoro-D-glucose-positron emission tomography (PET)/computed tomography, PET/magnetic resonance imaging (MRI), or diffusion-weighted MRI seem to be promising in diagnosis and follow-up. Finding the causative pathogen is of utmost importance followed by long-term intravenous antibiotics until the disease has completely resolved. Surgery plays a minor role in treatment but can be helpful in selected cases.

The numerous challenges in SBO render management difficult, but with a clear work-up including regular clinical, laboratory and imaging examinations, outcome can be improved.
Cytoplasmic P120ctn Promotes Gefitinib Resistance in Lung Cancer Cells by Activating PAK1 and ERK Pathway
Authors: Liu Wei-Wei , Hu Jing , Wang Rui , Han Qiang , Liu Yang , Wang Si
Published: August 2021

Our previous studies indicated that cytoplasmic p120ctn mediated epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) resistance in lung cancer. In the present study, we aim to further explore the underlying molecular mechanisms. Immunohistochemistry detected PAK1, Cdc42, and Rac1 expression in lung cancer with cytoplasmic p120ctn. Immunoblotting, protein activity analysis, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide evaluated p120ctn location, PAK1, Cdc42/Rac1, and extracellular signal-regulated kinase (ERK) activity in response to TKI treatment in HCC827 and PC9 cell lines, as well as the cell sensitivity to Gefitinib. Most non-small cell lung cancer patients with cytoplasmic p120ctn showed enhanced PAK1 and Cdc42/Rac1. When Gefitinib resistance was induced, cytoplasmic p120ctn is accompanied with increasing PAK1 and Cdc42/Rac1. Cytoplasmic p120ctn activated ERK via PAK1, while PAK1 downregulation attenuated ERK activation by cytoplasmic p120ctn. After Cdc42/Rac1 inhibition, cytoplasmic p120ctn could not activate PAK1. Cytoplasmic p120ctn activates PAK1 via Cdc42/Rac1 activation, constitutively activates ERK in the EGFR downstream signaling, and promotes EGFR-TKI resistance in lung cancer cells. The current study will aid to screen the subpopulation patients who would benefit from therapy with first-generation EGFR-TKIs.
Risk Factors for Loss to Follow-Up in the Lower Extremity Limb Salvage Population
Authors: Sharif-Askary Banafsheh , Zolper Elizabeth G. , Deldar Romina , Tefera Eshetu , Tirrell Abigail R. , Abu El Hawa Areeg A. , Attinger Christopher E. , Evans Karen K. , Fan Kenneth L.
Published: August 2021

Background:

Limb salvage for chronic lower extremity wounds requires long-term care best delivered by specialized multidisciplinary centers. This optimizes function, reduces amputation rates, and improves mortality. These centers may be limited to urban/academic settings, making access and appropriate follow-up challenging. Therefore, the authors hypothesize that both system- and patient-related factors put this population at exceedingly high risk for loss to follow-up.

Methods:

Records were reviewed retrospectively for 200 new patients seen at the Georgetown Center for Wound Healing in 2013. The primary outcome was loss to follow-up, defined as three consecutive missed appointments despite explicit documentation indicating the need for return visits. Demographic, clinical, and geographic data were compared. Multivariate logistic regression analysis for loss to follow-up status controlled for variables found significant in the bivariate analysis. Spatial dependency was evaluated using variograms.

Results:

Over a 6.5-year-period, 49.5 percent of patients followed were lost to follow-up. Male sex and increased driving distance to the limb salvage center were risk factors for loss to follow-up. Wound-specific characteristics including ankle and knee/thigh location were also associated with higher rates of loss to follow-up. There was no spatial dependency or discrete clustering of at-risk patients.

Conclusions:

This study is the first of its kind to investigate the demographic and clinical characteristics that predispose chronic lower extremity wound patients to loss to follow-up. These findings inform stakeholders of the high rates of loss to follow-up and support decentralized specialty care, in the form of telemedicine, satellite facilities, and/or dedicated case managers. Future work will focus on targeting vulnerable populations through focused interventions to reduce patient and system burden.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, III.
Long-Term Follow-Up After Unilateral Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy: The RESTORE Study
Authors: Biousse Valérie , Newman Nancy J. , Yu-Wai-Man Patrick , Carelli Valerio , Moster Mark L. , Vignal-Clermont Catherine , Klopstock Thomas , Sadun Alfredo A. , Sergott Robert C. , Hage Rabih , Esposti Simona , La Morgia Chiara , Priglinger Claudia , Karanja Rustum , Blouin Laure , Taiel Magali , Sahel José-Alain ,   for the LHON Study Group
Published: August 2021

Background:

RESCUE and REVERSE were 2 Phase 3 clinical trials that assessed the efficacy and safety of intravitreal gene therapy with lenadogene nolparvovec (rAAV2/2-ND4) for the treatment of Leber hereditary optic neuropathy (LHON). RESTORE is the long-term follow-up study of subjects treated in the RESCUE and REVERSE trials.

Methods:

In RESCUE and REVERSE, 76 subjects with LHON because of the m.11778 G>A mutation in the mitochondrial gene ND4 received a single unilateral intravitreal injection of lenadogene nolparvovec. After 96 weeks, 61 subjects were enrolled in the long-term follow-up study RESTORE. The best-corrected visual acuity (BCVA) was assessed over a period of up to 52 months after onset of vision loss. A locally estimated scatterplot smoothing regression model was used to analyze changes in BCVA over time. Vision-related quality of life was reported using the visual function questionnaire-25 (VFQ-25).

Results:

The population of MT-ND4 subjects enrolled in RESTORE was representative of the combined cohorts of RESCUE and REVERSE for mean age (35.1 years) and gender distribution (79% males). There was a progressive and sustained improvement of BCVA up to 52 months after the onset of vision loss. The final mean BCVA was 1.26 logarithm of the minimal angle of resolution 48 months after the onset of vision loss. The mean VFQ-25 composite score increased by 7 points compared with baseline.

Conclusion:

The treatment effect of lenadogene nolparvovec on BCVA and vision-related quality of life observed 96 weeks (2 years) after treatment in RESCUE and REVERSE was sustained at 3 years in RESTORE, with a maximum follow-up of 52 months (4.3 years) after the onset of vision loss.
Infection with the SARS-CoV-2 Delta Variant is Associated with Higher Infectious Virus Loads Compared to the Alpha Variant in both Unvaccinated and Vaccinated Individuals
Authors: Luo Chun Huai , Morris C. Paul , Sachithanandham Jaiprasath , Amadi Adannaya , Gaston David , Li Maggie , Swanson Nicholas J. , Schwartz Matthew , Klein Eili Y. , Pekosz Andrew , Mostafa Heba H.
Published: August 2021

Background

The emerging SARS-CoV-2 variant of concern (VOC) B.1.6.17.2 (Delta) quickly displaced the B.1.1.7 (Alpha) and is associated with increases in COVID-19 cases nationally. The Delta variant has been associated with greater transmissibility and higher viral RNA loads in both unvaccinated and fully vaccinated individuals. Data is lacking regarding the infectious virus load in Delta infected individuals and how that compares to individuals infected with other SARS-CoV-2 lineages.

Methods

Whole genome sequencing of 2,785 clinical isolates was used to characterize the prevalence of SARS-CoV-2 lineages circulating in the National Capital Region between January and July 2021. Clinical chart reviews were performed for the Delta, Alpha, and B.1.2 (a control predominant lineage prior to both VOCs) variants to evaluate disease severity and outcome and Cycle threshold values (Cts) were compared. The presence of infectious virus was determined using Vero-TMPRSS2 cells and anti-SARS-CoV-2 IgG levels were determined from upper respiratory specimen. An analysis of infection in unvaccinated and fully vaccinated populations was performed.

Results

The Delta variant displaced the Alpha variant to constitute 88.2% of the circulating lineages in the National Capital Region by July, 2021. The Delta variant associated with increased breakthrough infections in fully vaccinated individuals that were mostly symptomatic when compared to the Alpha breakthrough infections, though it is important to note there was a significantly longer period of time between vaccination and infection with Delta infections. The recovery of infectious virus on cell culture was significantly higher with the Delta variant compared to Alpha in both vaccinated and unvaccinated groups. The impact of vaccination on reducing the recovery of infectious virus from clinical samples was only observed with Alpha variant infections but was strongly associated with low localized SARS-CoV-2 IgG for both variants. A comparison of Ct values showed a significant decrease in the Delta compared to Alpha with no significant differences between unvaccinated and vaccinated groups.

Conclusions

Our data indicate that the Delta variant is associated with increased infectious virus loads when compared to the Alpha variant and decreased upper respiratory antiviral IgG levels. Measures to reduce transmission in addition to increasing vaccinations rates have to be implemented to reduce Delta variant spread.

Funding

NIH/NIAID Center of Excellence in Influenza Research and Surveillance contract HHS N2772201400007C, Johns Hopkins University, Maryland department of health, Centers for Disease Control and Prevention contract 75D30121C11061.
Association of COVID-19 vaccination with risks of hospitalization due to cardiovascular and other diseases: A study of the UK
Authors: Xiang Yong , Feng Yaning , Qiu Jinghong , Zhang Ruoyu , So Hon-Cheong
Published: August 2021

Background

Vaccines for COVID-19 represent a major breakthrough. However, worries about adverse effects led to vaccine hesitancy in some people. On the other hand, as COVID-19 may be associated with various sequelae, vaccination may protect against such sequelae via prevention of infections and severe disease.

Methods

We leveraged the UK-Biobank (UKBB) and studied associations of at least one dose of COVID-19 vaccination (BioNTech-BNT162b2 or Oxford-AstraZeneca-ChAdOx1) with short-term hospitalizations from cardiovascular and other selected diseases (N=393,544; median follow-up=54 days among vaccinated). Multivariable Cox and Poisson regression analyses were performed. We also performed adjustment using prescription-time distribution matching (PTDM) and prior-event rate ratio (PERR). PERR minimizes unmeasured confounding by comparing event hazards before introduction of vaccination.

Results

We observed that COVID-19 vaccination(at least one dose), when compared to no vaccination, was associated with reduced short-term risks of hospitalizations from stroke(hazard ratio[HR]=0.178, 95% CI: 0.127-0.250,P=1.50e-23), venous thromboembolism (VTE) (HR=0.426, CI: 0.270-0.673,P=2.51e-4), dementia(HR=0.114, CI: 0.060-0.216;P=2.24e-11), non-COVID-19 pneumonia(NCP) (HR=0.108, CI: 0.080-0.145;P=2.20e-49), coronary artery disease (CAD) (HR=0.563, CI: 0.416-0.762;P=2.05e-4), chronic obstructive pulmonary disease (COPD) (HR=0.212, CI: 0.126-0.357;P=4.92e-9), type-2 diabetes (T2DM) (HR=0.216, CI: 0.096-0.486,P=2.12e-4), heart failure (HR=0.174, CI: 0.118-0.256,P=1.34e-18) and renal failure (HR=0.415, CI: 0.255-0.677,P=4.19e-4), based on Cox regression models. Among the above results, reduced hospitalizations for stroke, heart failure, NCP and dementia were consistently observed across all analyses, including regression/PTDM/PERR.

Conclusions

Taken together, this study provides further support to the safety and benefits of COVID-19 vaccination, and such benefits may extend beyond reduction of infection risk or severity per se. However, causal relationships cannot be concluded and further studies are required to verify the findings.
COVID-19 ASSOCIATED MUCORMYCOSIS: A CASE-CONTROL STUDY
Authors: Gupta Dulari , Kulkarni Rahul , Pujari Shripad , Mulay Atul
Published: August 2021

Background

India has seen a surge in COVID-19 associated mucormycosis (CAM) cases during the second wave of the pandemic. We conducted a study to determine independent risk factors for CAM.

Methods

We performed a retrospective case control study in a tertiary care private hospital in Pune, India. Fifty-two cases of CAM were compared with 166 concurrent controls randomly selected from the COVID-19 admissions during the same time period. Association of demographic factors, comorbidities, cumulative steroid dose used (calculated as dexamethasone equivalent), maximum respiratory support required, use of injectable/oral anticoagulation, and use of aspirin with CAM was assessed by univariate and multivariate logistic regression.

Results

A total of 218 subjects (52 cases; 166 controls) were studied. Any diabetes (pre-existing diabetes and new onset diabetes during COVID-19) was noted in a significantly higher proportion of cases (73·1%, 45·8% P<0.001) and cumulative dexamethasone dose used in cases was significantly greater (97·72 mg vs 60 mg; P=0·016). In a multivariate regression analysis cumulate dexamethasone dose >120 mg (OR 9·03, confidence interval 1·75-46·59, P=0·009) and any diabetes (OR 4·78, confidence interval 1·46-15·65, P=0·01) were found to be risk factors for CAM. While use of anticoagulation (OR 0·01, confidence interval 0·00-0·09, P<0·001) and use of aspirin (OR 0·02, confidence interval 0·01-0·07, P<0·001) were found to be protective against CAM.

Conclusion

Diabetes mellitus and cumulative dose of dexamethasone greater than 120 mg (or equivalent dose of other corticosteroid) were associated with an increased risk of CAM while use of aspirin and anticoagulation were associated with a lower risk.
SARS-CoV-2 aerosol transmission in schools: the effectiveness of different interventions
Authors: Villers Jennifer , Henriques Andre , Calarco Serafina , Rognlien Markus , Mounet Nicolas , Devine James , Azzopardi Gabriella , Elson Philip , Andreini Marco , Tarocco Nicola , Vassella Claudia , Keiser Olivia
Published: August 2021

Abstract

Background

Indoor aerosol transmission of SARS-CoV-2 has been widely recognized, especially in schools where children remain in closed indoor spaces and largely unvaccinated. Measures such as strategic natural ventilation and high efficiency particulate air (HEPA) filtration remain poorly implemented and mask mandates are often progressively lifted as vaccination rollout is enhanced.

Methods

We adapted a previously developed aerosol transmission model to study the effect of interventions (natural ventilation, face masks, HEPA filtration, and their combinations) on the concentration of virus particles in a classroom of 160 m3 containing one infectious individual. The cumulative dose of viruses absorbed by exposed occupants was calculated.

Results

The most effective single intervention was natural ventilation through the full opening of six windows all day during the winter (14-fold decrease in cumulative dose), followed by the universal use of surgical face masks (8-fold decrease). In the spring/summer, natural ventilation was only effective (≥ 2-fold decrease) when windows were fully open all day. In the winter, partly opening two windows all day or fully opening six windows at the end of each class was effective as well (≥ 2-fold decrease). Opening windows during yard and lunch breaks only had minimal effect (≤ 1.2-fold decrease). One HEPA filter was as effective as two windows partly open all day during the winter (2.5-fold decrease) while two filters were more effective (4-fold decrease). Combined interventions (i.e., natural ventilation, masks, and HEPA filtration) were the most effective (≥ 30-fold decrease). Combined interventions remained highly effective in the presence of a super-spreader.

Conclusions

Natural ventilation, face masks, and HEPA filtration are effective interventions to reduce SARS-CoV-2 aerosol transmission. These measures should be combined and complemented by additional interventions (e.g., physical distancing, hygiene, testing, contact tracing, and vaccination) to maximize benefit.
Serial interval and transmission dynamics during the SARS-CoV-2 Delta variant predominance in South Korea
Authors: Ryu Sukhyun , Kim Dasom , Lim Jun-Sik , Ali Sheikh Taslim , Cowling Benjamin J.
Published: August 2021

We estimated mean serial interval and superspreading potential for the predominant Delta variant of SARS-CoV-2. Mean serial intervals were similar with 3.7 and 3.5 days during early and latter periods, respectively. Furthermore, the risk of superspreading events was similar with 23% and 25% of cases seeded 80% of all transmissions.
Spinal cord synaptic plasticity by GlyRβ release from receptor fields and syndapin-dependent uptake
Authors: Tröger Jessica , Seemann Eric , Heintzmann Rainer , Kessels Michael M. , Qualmann Britta
Published: August 2021

Glycine receptor-mediated inhibitory neurotransmission is key for spinal cord function. Recent observations suggested that by largely elusive mechanisms also glycinergic synapses display synaptic plasticity. We here identify syndapin I as critical player. Interestingly, syndapin I cooperates but in part also competes with gephyrin. Syndapin I deficiency led to fragmentation of glycine receptor fields, more disperse receptors and increased receptor mobility. Kainate treatment highlighted syndapin I’s importance even more. Our analyses unveiled that PKC-mediated S403 phosphorylation-mediated glycine receptor β decoupling from gephyrin scaffolds simultaneously promoted syndapin I association. In line, kainate-treated syndapin I KO spinal cords showed even more severe receptor field fragmentation. Furthermore, syndapin I deficiency completely disrupted kainate-induced glycine receptor internalization. Together, this unveiled important mechanisms controlling the number and organization of glycine receptor fields at inhibitory postsynapses during both steady-state and kainate-induced synaptic rearrangement - principles organizing and fine-tuning synaptic efficacy of inhibitory synapses in the spinal cord.
ReporterSeq reveals genome-wide determinants of proteasome expression
Authors: Work Jeremy J. , Alford Brian D. , Dea Annisa , Ali Asif , Pincus David , Brandman Onn
Published: August 2021

The ubiquitin-proteasome system (UPS) is critical for cellular and organismal health. To uncover mechanisms regulating the UPS in normal and stress conditions, we systematically probed the genome of the eukaryotic model system Saccharomyces cerevisiae for modulators of the UPS master regulator Rpn4 under basal and stress conditions using the reverse genetic method ReporterSeq. The top UPS regulators were the thioredoxin reductase Trr1 and proteins of the large ribosomal subunit, both of which had no previously known role in UPS regulation. Unlike all known mechanisms for Rpn4 regulation which regulate Rpn4 levels, we found that Trr1 modulates the molecular activity of Rpn4 and does so in response to oxidative stress. Our work illuminates the genetic landscape through which cells regulate the UPS, and provides insight into how cells combat proteotoxicity.
The DNA sensors AIM2 and IFI16 are NET-binding SLE autoantigens
Authors: Antiochos Brendan , Fenaroli Paride , Rosenberg Avi , Baer Alan N. , Sohn Jungsan , Li Jessica , Petri Michelle , Goldman Daniel W. , Mecoli Christopher , Casciola-Rosen Livia , Rosen Antony
Published: August 2021

Nucleic acid binding proteins are frequently targeted as autoantigens in systemic lupus erythematosus (SLE) and other interferon (IFN)-linked rheumatic diseases. The AIM-like receptors (ALRs) are IFN-inducible innate sensors that form supramolecular assemblies along double-stranded DNA of various origins. Here, we identify the ALR Absent in melanoma 2 (AIM2) as a novel autoantigen in SLE, with similar properties to the established ALR autoantigen interferon-inducible protein 16 (IFI16). Our SLE cohort revealed a frequent co-occurrence of anti-AIM2, anti-IFI16 and anti-DNA antibodies, and higher clinical measures of disease activity in patients positive for antibodies against these ALRs. We examined neutrophil extracellular traps (NETs) as DNA scaffolds on which these antigens might interact in a pro-immune context, finding that both ALRs bind NETs in vitro and in SLE renal tissues. We demonstrate that ALR binding causes NETs to resist degradation by DNase I, suggesting a mechanism whereby extracellular ALR-NET interactions may promote sustained IFN signaling. Our work suggests that extracellular ALRs bind NETs, leading to DNase resistant nucleoprotein fibers that are targeted as autoantigens in SLE.
Multi view based imaging genetics analysis on Parkinson disease
Authors: Cerri Guglielmo , Tognon Manuel , Avesani Simone , Oxtoby Neil P. , Altmann Andre , Giugno Rosalba
Published: August 2021

Longitudinal studies integrating imaging and genetic data have recently become widespread among bioinformatics researchers. Combining such heterogeneous data allows a better understanding of complex diseases origins and causes. Through a multi-view based workflow proposal, we show the common steps and tools used in imaging genetics analysis, interpolating genotyping, neuroimaging and transcriptomic data. We describe the advantages of existing methods to analyze heterogeneous datasets, using Parkinson’s Disease (PD) as a case study. Parkinson’s disease is associated with both genetic and neuroimaging factors, however such imaging genetics associations are at an early investigation stage. Therefore it is desirable to have a free and open source workflow that integrates different analysis flows in order to recover potential genetic biomarkers in PD, as in other complex diseases.
CNest: A Novel Copy Number Association Discovery Method Uncovers 862 New Associations from 200,629 Whole Exome Sequence Datasets in the UK Biobank
Authors: Fitzgerald Tomas , Birney Ewan
Published: August 2021

Copy number variation (CNV) has long been known to influence human traits having a rich history of research into common and rare genetic disease and although CNV is accepted as an important class of genomic variation, progress on copy number (CN) phenotype associations from Next Generation Sequencing data (NGS) has been limited, in part, due to the relative difficulty in CNV detection and an enrichment for large numbers of false positives. To date most successful CN genome wide association studies (CN-GWAS) have focused on using predictive measures of dosage intolerance or gene burden tests to gain sufficient power for detecting CN effects. Here we present a novel method for large scale CN analysis from NGS data generating robust CN estimates and allowing CN-GWAS to be performed genome wide in discovery mode. We provide a detailed analysis in the large scale UK BioBank resource and a specifically designed software package for deriving CN estimates from NGS data that are robust enough to be used for CN-GWAS. We use these methods to perform genome wide CN-GWAS analysis across 78 human traits discovering 862 genetic associations that are likely to contribute strongly to trait distributions based solely on their CN or by acting in concert with other genetic variation. Finally, we undertake an analysis comparing CNV and SNP association signals across the same traits and samples, defining specific CNV association classes based on whether they could be detected using standard SNP-GWAS in the UK Biobank.
Iron oxidation is regulated by the two-component system, RegSR, and plays a role in photolithoheterotrophic growth in Rhodopseudomonas palustris
Authors: Haas Nicholas W. , Jain Abhiney , Hying Zachary , Arif Sabrina J. , Gralnick Jeffrey A. , Fixen Kathryn R.
Published: August 2021

Purple nonsulfur bacteria (PNSB) are metabolically versatile organisms generate energy through both aerobic and anaerobic respiration as well as anoxygenic photosynthesis. In many PNSB, the redox-sensing, two-component system RegBA is a global regulator of energy generating and consuming pathways, such as photosynthesis, carbon fixation, and nitrogen fixation, when cells are shifted from an aerobic to an anaerobic environment. However, in the PNSB Rhodopseudomonas palustris, the role of the RegBA homolog, RegSR, was unclear since global regulation of these same pathways involves the oxygen-sensing signal transduction system, FixJL-K, in R. palustris. Using RNA-seq analysis, we found that RegSR plays a role in regulating the operon pioABC, which encodes genes required for Fe(II) oxidation. We found that transcript levels of pioABC under photoheterotrophic conditions was dependent on the oxidation state of the carbon substrate and whether the cells were fixing nitrogen. We also found that R. palustris can carry out photolithoheterotrophic growth using Fe(II) oxidation when grown with the oxidized carbon substrate, malate, requiring regSR and pioABC. We present a model in which RegSR regulates pioABC in response to a cellular redox signal, allowing R. palustris to use Fe(II) oxidation to access more electrons when there is an increased cellular demand for reducing equivalents.

Significance

Mixotrophy is thought to be widespread in aquatic environments, yet little is understood about how mixotrophy affects biogeochemical cycles. Fe(II)-oxidizing anoxygenic phototrophs likely play an important role in iron cycling since they are thought to have thrived in the anoxic, iron-rich oceans of early Earth and can be found in both freshwater and marine environments. Although Fe(II) oxidation by anoxygenic phototrophs is largely studied in the context of photoautotrophic growth, these organisms can also grow photoheterotrophically. We present the first evidence linking photolithoheterotrophic growth using Fe(II) to the pathway required for photoautotrophic Fe(II) oxidation in an anoxygenic phototroph. Understanding this metabolism will be important for understanding how mixotrophic metabolism contributes to iron cycling in anoxic environments.
Fatty acid-binding proteins and fatty acid synthase influence glial reactivity and promote the formation of Müller glia-derived progenitor cells in the avian retina
Authors: Campbell Warren A. , Tangeman Allen , El-Hodiri Heithem M. , Hawthorn Evan C. , Hathoot Maddie , Hoang Thanh , Blackshaw Seth , Fischer Andy J.
Published: August 2021

The capacity for retinal regeneration varies greatly across vertebrates species. A recent comparative epigenetic and transcriptomic investigation of Müller glial (MG) in the retinas of fish, birds and mice revealed that Fatty Acid Binding Proteins (FABPs) are among the most highly up-regulated genes in activated chick MG (Hoang et al., 2020). Herein we provide an in-depth follow-up investigation to describe patterns of expression and how FABPs and fatty acid synthase (FASN) influence glial cells in the chick retina. During development, FABP7 is highly expressed by embryonic retinal progenitor cells (eRPCs) and maturing MG, whereas FABP5 is gradually up-regulated in maturing MG and remains elevated in mature glial cells. PMP2 (FABP8) is expressed by oligodendrocytes and FABP5 is expressed by non-astrocytic inner retinal glial cells, and both of these FABPs are significantly up-regulated in activated MG in damaged or growth factor-treated retinas. In addition to suppressing the formation of MGPCs, we find that FABP-inhibition suppressed the accumulation of proliferating microglia, although the microglia appeared highly reactive. scRNA-seq analyses of cells treated with FABP-inhibitor revealed distinct changes in patterns of expression suggesting that FABPs are involved in the transitions of MG from a resting state to a reactive state and conversion from reactive MG to MGPCs. Inhibition of FABPs in undamaged retinas had a significant impact upon the transcriptomic profiles of MG, with up-regulation of genes associated with gliogenesis, decreases in genes associated with neurogenesis, and suppression of the ability of MG to become MGPCs. scRNA-seq analyses of microglia indicated that FABP inhibition enhances gene modules related to reactivity, proliferation and cytokine signaling. We find that the proliferation of retinal progenitors in the circumferential marginal zone (CMZ) is unaffected by FABP-inhibitor. Upstream of FABP activity, we inhibited FASN in damaged retinas, which reduced numbers of dying cells, increased the proliferation of microglia, and potently suppressed the formation MGPCs in damaged retinas. We conclude that the activity of FASN and FABPs are required early during the formation of proliferating MGPCs. Fatty acid metabolism and cell signaling involving fatty acids are important in regulating glial homeostasis in the retina, and the dedifferentiation and proliferation of microglia and MGPCs.
TomatoCRABS CLAWparalogues interact with chromatin remodelling factors to mediate carpel development and floral determinacy
Authors: Castañeda Laura , Giménez Estela , Pineda Benito , García-Sogo Begoña , Ortiz-Atienza Ana , Micol-Ponce Rosa , Angosto Trinidad , Capel Juan , Moreno Vicente , Yuste-Lisbona Fernando J. , Lozano Rafael
Published: August 2021

CRABS CLAW(CRC) orthologues play a crucial role in floral meristem (FM) determinacy and gynoecium formation across angiosperms, key developmental processes for ensuring successful plant reproduction and crop production. Here, we revealed that the incomplete penetrance and variable expressivity of the carpel-inside-carpel phenotype observed in flowers of the tomatofruit iterative growth(fig) mutant is due to a lack of function of a homologue of theCRCgene,Solanum lycopersicum CRCa(SlCRCa). Likewise, a comprehensive functional analysis ofSlCRCaandSlCRCbparalogues, including Arabidopsis complementation experiments, allowed us to propose that they operate as positive regulators of FM determinacy by acting in a compensatory and partially redundant manner to safeguard the proper formation of flowers and fruits. Furthermore, we provide the first evidence for the role of putativeCRCorthologues as members of the chromatin remodelling complex that terminates floral stem cell activity by repressingWUSCHELexpression.
Ecological conditions experienced by bat reservoir hosts predict the intensity of Hendra virus excretion over space and time
Authors: Becker Daniel J. , Eby Peggy , Madden Wyatt , Peel Alison J. , Plowright Raina K.
Published: August 2021

The ecological conditions experienced by wildlife reservoir hosts affect the amount of pathogen they excrete into the environment. This then shapes pathogen pressure, the amount of pathogen available to recipient hosts over space and time, which affects spillover risk. Few systems have data on both long-term ecological conditions and pathogen pressure, yet such data are critical for advancing our mechanistic understanding of ecological drivers of spillover risk. To identify these ecological drivers, we here reanalyze shedding data from a spatially replicated, multi-year study of Hendra virus excretion from Australian flying foxes in light of 25 years of long-term data on changing ecology of the bat reservoir hosts. Using generalized additive mixed models, we show that winter virus shedding pulses, previously considered idiosyncratic, are most pronounced after recent food shortages and in bat populations that have been displaced to novel habitats. We next derive the area under each annual shedding curve (representing cumulative virus excretion) and show that pathogen pressure is also affected by the ecological conditions experienced by bat populations. Finally, we illustrate that pathogen pressure positively predicts observed spillover frequency. Our study suggests that recent ecological conditions of flying fox hosts are shifting the timing, magnitude, and cumulative intensity of Hendra virus shedding in ways that shape the landscape of spillover risk. This work provides a mechanistic approach to understanding and estimating risk of spillover from reservoir hosts in complex ecological systems and emphasizes the importance of host ecological context in identifying the determinants of pathogen shedding.
Single-cell transcriptomic assessment of cellular phenotype stability in human precision-cut lung slices
Authors: Winters Nichelle I. , Taylor Chase J. , Jetter Christopher S. , Camarata Jane E. , Gutierrez Austin J. , Bui Linh T. , Gokey Jason J. , Bacchetta Matthew , Banovich Nicholas E. , Sucre Jennifer M.S. , Kropski Jonathan A.
Published: August 2021

Precision-cut lung slices (PCLS) are increasingly utilized for ex vivo disease modeling, but a high-resolution characterization of cellular phenotype stability in PCLS has not been reported. Comparing the single-cell transcriptomic profile of human PCLS after five days of culture to freshly isolated human lung tissue, we found striking changes in endothelial cell and alveolar epithelial cell programs, reflecting both injury and pathways activated in static culture, while immune cell frequencies and programs remained largely intact and similar to the native lung. These cellular dynamics should be considered when utilizing PCLS as a model of the human lung.
Cellulose synthase-like D (CSLD) proteins move in the plasma membrane and their targeting to cell tips, but not cell plates, depends on the actin cytoskeleton
Authors: Wu Shu-Zon , Chaves Arielle M. , Li Rongrong , Bezanilla Magdalena , Roberts Alison W.
Published: August 2021

Cellulose Synthase-Like D (CSLD) proteins are implicated in cell wall remodeling during tip growth and cell division in plants, and are known to generate β-1,4-glucan. It is unknown whether they form complexes and move in the plasma membrane like members of the Cellulose Synthase (CESA) family. We used the genetically tractable moss Physcomitrium patens, which has a filamentous protonemal stage that undergoes both tip growth and cell division and is amenable to high resolution live cell imaging, to investigate CSLD function and intracellular trafficking. CSLD2 and CSLD6 are highly expressed in gametophores and are redundantly required for gametophore cellular patterning. Live cell imaging revealed that CSLD6 is also expressed in protonemata where it moves in the plasma membrane and localizes to cell plates and cell tips. Notably, delivery to the apical plasma membrane, but not the cell plate, depends on actin. By comparing the behavior of endogenously tagged CSLD6 and CESA10, we discovered that CSLD6 movements in the plasma membrane were significantly faster, shorter in duration and less linear than CESA10 movements and were insensitive to the cellulose synthesis inhibitor isoxaben. These data suggest that CSLD6 and CESA10 function within different structures and may thus produce structurally distinct cellulose microfibrils.
Assessment of Carbon Sequestration Potential of some Selected Urban Tree Species
Authors: Ajayi Ezekiel
Published: August 2021

Tree species carbon assessment and quantification remain the only opportunity to determine the position of forest in climate change amelioration potentials. Forest biomass constitutes the largest terrestrial carbon sink and accounts for approximately 90% of all living terrestrial biomass. The aim of this study is to assess tree species carbon sequestration potentials of selected urban tree species. The study was carried out in Adekunle Ajasin University Campus, Akungba Akoko, Ondo State, Nigeria. All trees species ≥10 cm Diameter at Breast Height (Dbh) within the area were identified and their Dbh measured as well as other variables for volume computation such as height, diameters at the base, middle and top. Also, for density assessment; stem core samples were collected. Again, the coordinate of individual tree was recorded using a Global Positioning System (GPS) receiver. A total of 124 individual trees were encountered with varying growth variables as well as carbon values. The study area contains some indigenous and exotic tree species such asAcacia auriculiformis, Terminalia mantily, Gmelina arboreaandTectona grandisetc. butAcacia auriculiformishad the highest frequency. The tree species with highest carbon sequestration wasGmelina arboreaas recorded for this study. The total carbon and carbon dioxide sequestered in the study area were reported as 47.94 kg and 176.03 kg respectively.
Vectorial Channeling as a Mechanism for Translational Control by Functional Prions and Condensates
Authors: Gu Xinyu , Schafer Nicholas P. , Wolynes Peter G.
Published: August 2021

Translation of messenger RNA is regulated through a diverse set of RNA-binding proteins. A significant fraction of RNA-binding proteins contain prion-like domains which form functional prions. This raises the question of how prions can play a role in translational control. Local control of translation in dendritic spines by prions has been invoked in the mechanism of synaptic plasticity and memory. We show how channeling through diffusion and processive translation cooperate in highly ordered mRNA/prion aggregates as well as in less ordered mRNA/protein condensates depending on their sub-structure. We show the direction of translational control, whether it is repressive or activating, depends on the polarity of the mRNA distribution in mRNA/prion assemblies which determines whether vectorial channeling can enhance recycling of ribosomes. Our model also addresses the effect of changes of substrate concentration in assemblies that have been suggested previously to explain translation control by assemblies through the introduction of a potential of mean force biasing diffusion of ribosomes inside the assemblies. The results from the model are compared with the experimental data on translational control by two functional RNA-binding prions, CPEB involved in memory and Rim4 involved in gametogenesis.

Significance Statement

mRNA/protein assemblies such as functional prions and condensates are involved in locally regulating translation in eukaryotic cells. The mode of regulation depends on the structure of these assemblies. We show that the vectorial processive nature of translation can couple to transport via diffusion so as to repress or activate translation depending on the structure of the RNA protein assembly. We find that multiple factors including diffusivity changes and free energy biases in the assemblies can regulate the translation rate of mRNA by changing the balance between substrate recycling and competition between mRNAs. We mainly focus on the example of CPEB, a functional prion that has been implicated in the mechanism of synaptic plasticity of neurons and in memory.
Multiomics reveals persistence of obesity-associated immune cell phenotypes in adipose tissue during weight loss and subsequent weight regain
Authors: Cottam Matthew A. , Caslin Heather L. , Winn Nathan C. , Hasty Alyssa H.
Published: August 2021

Most individuals do not maintain weight loss, and weight regain increases cardio-metabolic risk beyond that of obesity. Adipose inflammation directly contributes to insulin resistance; however, immune-related changes that occur with weight loss and weight regain are not well understood. Single cell RNA-sequencing was completed with CITE-sequencing and biological replicates to profile changes in murine immune subpopulations following obesity, weight loss, and weight cycling. Weight loss normalized glucose tolerance, however, type 2 immune cells did not repopulate adipose following weight loss. Many inflammatory populations persisted with weight loss and increased further following weight regain. Obesity drove T cell exhaustion and broad increases in antigen presentation, lipid handing, and inflammation that persisted with weight loss and weight cycling. This work provides critical groundwork for understanding the immunological causes of weight cycling-accelerated metabolic disease. Thus, we have created an open-access interactive portal for our processed data to improve accessibility for the research community.
Molecular basis for GIGYF-TNRC6 complex assembly in miRNA-mediated translational repression
Authors: Sobti Meghna , Mead Benjamin J. , Igreja Cátia , Stewart Alastair G. , Christie Mary
Published: August 2021

The GIGYF proteins associate with 4EHP and RNA-associated proteins to elicit transcript-specific translational repression. However, the mechanism by which the GIGYF1/2-4EHP complex is recruited to its target transcripts remain unclear. Here we report the crystal structures of the GYF domains from GIGYF1 and GIGYF2 in complex with proline-rich sequences from miRISC-binding proteins TNRC6C and TNRC6A, respectively. The TNRC6 proline-rich motifs bind to a conserved array of aromatic residues on the surface of the GIGYF1/2 GYF domain, bridging 4EHP to Argonaute-miRNA mRNA targets. Our structures also reveal a phenylalanine residue conserved from yeast to human GYF domains that contributes to GIGYF2 thermostability. The molecular details we outline here are likely to be conserved between GIGYF1/2 and other RNA-binding proteins to elicit 4EHP-mediated repression in different biological contexts.
CD4+CCR6+ T cells dominate the BCG-induced transcriptional signature
Authors: Singhania Akul , Dubelko Paige , Kuan Rebecca , Chronister William D. , Muskat Kaylin , Das Jyotirmoy , Phillips Elizabeth J. , Mallal Simon A. , Seumois Grégory , Vijayanand Pandurangan , Sette Alessandro , Lerm Maria , Peters Bjoern , Lindestam Arlehamn Cecilia S.
Published: August 2021

The century-oldMycobacterium bovisBacillus Calmette-Guerin (BCG) remains the only licensed vaccine against tuberculosis (TB). Despite this, there is still a lot to learn about the immune response induced by BCG, both in terms of phenotype and specificity. Here, we investigated immune responses in adult individuals pre and 8 months post BCG vaccination. We specifically determined changes in gene expression, cell subset composition, DNA methylome, and the TCR repertoire induced in PBMCs and CD4 memory T cells associated with antigen stimulation by either BCG or aMycobacterium tuberculosis(Mtb)-derived peptide pool. Following BCG vaccination, we observed increased frequencies of CCR6+ CD4 T cells, which includes both Th1* and Th17 subsets, and mucosal associated invariant T cells (MAITs). A large number of immune response genes and pathways were upregulated post BCG vaccination with similar patterns observed in both PBMCs and memory CD4 T cells, thus suggesting a substantial role for CD4 T cells in the cellular response to BCG. These upregulated genes and associated pathways were also reflected in the DNA methylome. We described both qualitative and quantitative changes in the BCG-specific TCR repertoire post vaccination, and importantly found evidence for similar TCR repertoires across different subjects. The immune signatures defined herein can be used to track and further characterize immune responses induced by BCG, and can serve as reference for benchmarking novel vaccination strategies.