bluuebunny/crossref_metadata_2025 huggingface dataset:
Stringent σ8 constraints from small-scale galaxy clustering using a hybrid MCMC + emulator framework
Authors: Yuan Sihan , Garrison Lehman H , Eisenstein Daniel J , Wechsler Risa H
Published: July 2022

We present a novel simulation-based hybrid emulator approach that maximally derives cosmological and Halo Occupation Distribution (HOD) information from non-linear galaxy clustering, with sufficient precision for DESI Year 1 (Y1) analysis. Our hybrid approach first samples the HOD space on a fixed cosmological simulation grid to constrain the high-likelihood region of cosmology + HOD parameter space, and then constructs the emulator within this constrained region. This approach significantly reduces the parameter volume emulated over, thus achieving much smaller emulator errors with fixed number of training points. We demonstrate that this combined with state-of-the-art simulations result in tight emulator errors comparable to expected DESI Y1 LRG sample variance. We leverage the new abacussummit simulations and apply our hybrid approach to CMASS non-linear galaxy clustering data. We infer constraints on σ8 = 0.762 ± 0.024 and fσ8(zeff = 0.52) = 0.444 ± 0.016, the tightest among contemporary galaxy clustering studies. We also demonstrate that our fσ8 constraint is robust against secondary biases and other HOD model choices, a critical first step towards showcasing the robust cosmology information accessible in non-linear scales. We speculate that the additional statistical power of DESI Y1 should tighten the growth rate constraints by at least another 50–60 ${{\ \rm per\ cent}}$, significantly elucidating any potential tension with Planck. We also address the ‘lensing is low’ tension, which we find to be in the same direction as a potential tension in fσ8. We show that the combined effect of a lower fσ8 and environment-based bias accounts for approximately $50{{\ \rm per\ cent}}$ of the discrepancy.
Functional assessment of military aircrew applicants in a hypobaric chamber
Authors: Ang T , Tan D , Goh B , Ng W T , Tan B B C , See B
Published: July 2022

Background

Aircrew are exposed to environmental pressure changes. In the Republic of Singapore Air Force (RSAF), applicants assessed to be at intermediate risk of otic barotrauma undergo a hypobaric chamber assessment [“trial of chamber” (TOC)] to functionally evaluate their suitability for military aircrew vocations.

Aims

To identify factors associated with TOC failure among applicants with otorhinolaryngological conditions.

Methods

All applicants to RSAF aircrew vocations who were assessed to be at intermediate risk of otic barotrauma over a 3-yr period were identified using the RSAF Aeromedical Centre’s electronic database. Their medical records, as well as the TOC assessment records of the subset of applicants who underwent TOC, were reviewed for demographic data, clinical findings, and TOC outcomes.

Results

Of the 483 identified applicants, 374 (77%) had abnormal otoscopic findings, 103 (21%) had rhinitis symptoms, and 6 (1%) had previous ENT surgery. 123 (25%) underwent TOC, of which 20 (16%) failed. Holding other predictor variables constant, the odds of TOC failure increased by 0.79 per unit decrease in BMI (95% CI 0.63–0.99), and the odds of TOC failure increased by 0.93 per kg decrease in body weight (95% CI 0.87–1.00). An abnormal tympanogram was not a statistically significant predictor of TOC failure (OR 1.96, 95% CI 0.59–6.42). Of the 47 applicants who passed TOC and were eventually recruited, none subsequently developed otic barotrauma (mean follow-up, 3.3 yr ± 1.5 yr).

Conclusions

Applicants with lower weight and BMI are more likely to develop otic barotrauma with environmental pressure change. Tympanometry cannot be reliably used to identify applicants who would more likely pass TOC.
Redescription, taxonomic revaluation and phylogenetic affinities of Proterochampsa nodosa (Archosauriformes: Proterochampsidae) from the early Late Triassic of the Candelaria Sequence (Santa Maria Supersequence)
Authors: De Simão-Oliveira Daniel , Pinheiro Felipe Lima , De Andrade Marco Brandalise , Pretto Flávio Augusto
Published: July 2022

Proterochampsidae are a group of predatory, putatively semi-aquatic, archosauriforms endemic to the Middle and Upper Triassic strata of Argentina and Brazil (Ischigualasto Formation and Santa Maria Supersequence). Here, the Brazilian species Proterochampsa nodosa from the Candelária Sequence (Santa Maria Supersequence of the Paraná Basin) is revisited with a detailed description, phylogenetic analysis and taxonomic revaluation. Through the application of computed tomographic scans, we were able to reveal part of the previously hidden morphology of its mandible and palate. We also discuss further differences between P. nodosa and P. barrionuevoi. The new phylogenetic analysis bolsters the monophyly of Proterochampsidae, the genus Proterochampsa and its position as the basalmost proterochampsid taxon in the clade.
Complete Margin Assessment Versus Sectional Assessment in Surgically Excised High-Risk Keratinocyte Carcinomas: A Systematic Review and Meta-Analysis
Authors: Fraga Sophia D. , Besaw Robert J. , Murad Fadi , Schmults Chrysalyne D. , Waldman Abigail
Published: July 2022

BACKGROUND

Keratinocyte carcinomas (KCs) are the most diagnosed cancers worldwide and are commonly excised via complete margin assessment (CMA) or excision with sectional assessment (SA). National Comprehensive Cancer Network guidelines encourage CMA for KC with high-risk features.

OBJECTIVE

To systematically compare recurrence outcomes for CMA vs SA in high-risk KC based on National Comprehensive Cancer Network guidelines criteria.

MATERIALS AND METHODS

EMBASE and MEDLINE were searched for articles reporting recurrences of high-risk KC undergoing excision using CMA or SA. High-risk KCs were defined as recurrent, having perineural invasion (PNI), or basal cell carcinomas (BCC) with aggressive histology. Chi-squared tests and risk ratios evaluated differences between CMA and SA groups, and a random-effects meta-analysis was performed.

RESULTS

Twenty-eight studies met inclusion criteria. Pooled percentages of locoregional recurrences were significantly lower with CMA vs SA for all KCs (3.9% [95% CI: 2.9–4.9] vs 13.5% [7.7, 19.2, p = .001]), cutaneous squamous cell carcinoma with PNI (9.8% [5.4–14.1] vs 32.0% [25.0–39.0], p < .001), and recurrent BCC (4.4% [2.9–5.9] vs 11.9% [8.0–15.8], p < .001).

CONCLUSION

For high-risk KCs, recurrence risk was over 3-times greater with SA compared with CMA. Expanded access to CMA for high-risk KC is likely to reduce recurrence risk and improve clinical outcomes.
Self-antigens, benign autoimmunity and type 1 diabetes: a beta-cell and T-cell perspective
Authors: Samassa Fatoumata , Mallone Roberto
Published: July 2022

Purpose of review

Recent work using immunopeptidomics and deconvolution of the antigenic reactivity of islet-infiltrating CD8+ T cells has expanded our knowledge about the autoimmune target epitopes of type 1 diabetes. The stem-like properties of autoimmune CD8+ T cells have also been described. We here propose a possible link between these findings.

Recent findings

Weak major histocompatibility complex (MHC)-binding epitopes list among the major targets of human islet-infiltrating CD8+ T cells, likely resulting in low peptide-MHC presentation that delivers weak T-cell receptor (TCR) signals, especially in the face of low-affinity autoimmune TCRs. These weak TCR signals may favor the maintenance of the partially differentiated stem-like phenotype recently described for islet-reactive CD8+ T cells in the blood and pancreatic lymph nodes. These weak TCR signals may also be physiological, reflecting the need for self-peptide-MHC contacts to maintain homeostatic T-cell survival and proliferation. These features may underlie the universal state of benign autoimmunity that we recently described, which is characterized by islet-reactive, naïve-like CD8+ T cells circulating in all individuals.

These observations provide novel challenges and opportunities to develop circulating T-cell biomarkers for autoimmune staging. Therapeutic halting of islet autoimmunity may require targeting of stem-like T cells to blunt their self-regeneration.
Life satisfaction and athletic identity among Olympic para-alpine skiers: a survey
Authors: Šuc Nika , Vidmar Gaj , Cecić Erpič Saša , Lešnik Blaž
Published: July 2022

The objective of this study was to examine life satisfaction and athletic identity among para-alpine skiers and explore their associations with sociodemographic, sports practice, and disability-related characteristics of the participants. The respondents to the on-site survey were 129 para-alpine ski racers with acquired disability from 33 countries on all five continents who competed in the Paralympic games in Sochi (aged 16–53 years, mean and median 30 years, 100 men). Two self-developed assessment instruments were used – a 7-point Likert-type life-satisfaction questionnaire probing seven domains (health, family, education, freedom, friends, travelling, and self) and the Athletic Identity Scale (AIS; possible score range 17–85). The independence between life-satisfaction items was confirmed by low interitem correlations (largest absolute value <0.25, 15 of 21, and <0.15). The estimated internal-consistency reliability (Guttman lambda-2) of AIS was 0.65. The reported life satisfaction was very high (median of 6 for all domains except education, where it was 5). Like life-satisfaction ratings, the AIS scores were also very high on average (mean and median score 81). In general, the level of life satisfaction and athletic identity were not notably associated with sociodemographic, sports practice, and disability characteristics of the participants. The likely reason is high average and, hence, low variability of life-satisfaction ratings, as well as imperfect metric characteristics of the AIS. Nonetheless, the overall findings encourage further research into factors that drive the participation of disabled athletes in (winter) Paralympic games and the possible role of the rehabilitation process in this regard.
Do heel-unloading orthoses improve clinical outcomes in patients after surgical treatment of calcaneal fracture? A propensity-matched, multicenter analysis of the TRON database
Authors: Kagami Yujiro , Tokutake Katsuhiro , Takegami Yasuhiko , Okui Nobuyuki , Sakai Tadahiro , Inoue Hidenori , Kanemura Tokumi , Hanabayashi Masahiro , Ito Osamu , Kanayama Yasuhide , Maruyama Koji , Yoshida Hiroaki , Ando Toshihiro , Sugimoto Ryosuke , Sugimoto Takuya , Imagama Shiro
Published: July 2022

Background:

Postoperative protocols after surgical treatment of calcaneal fracture have not been standardized to date. There are only a few reports on the efficacy of heel-unloading orthoses (HUOs; Mars shoe, Graffin orthosis), and thier efficacy is uncertain.

Objectives:

The purpose of this study was to compare postoperative radiologic and clinical outcomes in patients with calcaneal fractures who used Graffin orthosis.

Study design:

Multicenter retrospective study.

Methods:

We finally extracted 182 patients from a database of the Trauma Research Group of Nagoya and divided them into two groups: group C (underwent casting or splinting only) and group O (Graffin orthosis was used). A propensity score algorithm was used to match group C to group O in a 1:1 ratio. We evaluated American Orthopaedic Foot and Ankle Society (AOFAS) score at three and six months after surgery and at final follow-up. Differences in reduction of the Böhler angle between the two groups were evaluated radiographically. All data were analyzed with a t-test or Fisher’s exact test. P < .05 was considered statistically significant.

Results:

The AOFAS score 3 months after surgery in group O was significantly higher than that in group C (69.57 vs. 77.22; P = .004). However, there were no statistically significant differences between group C vs. group O in AOFAS scores at 6 months after surgery and at final follow-up (81.92 vs. 85.67 and 89.18 vs. 88.13; P = .087 and 0.597, respectively). There was no significant statistical difference in the reduction of the Böhler angle (5.07 vs. 5.89; P = .529).

Conclusions:

At 3 months postoperatively, the orthosis group showed predominantly better functional results. We believe that heel-unloading orthoses are useful for patients who require an early return to work and to daily life.
Spectral Shaping Via Tin Prefiltration in Ultra-High-Resolution Photon-Counting and Energy-Integrating Detector CT of the Temporal Bone
Authors: Grunz Jan-Peter , Heidenreich Julius Frederik , Lennartz Simon , Weighardt Jens Philipp , Bley Thorsten Alexander , Ergün Süleyman , Petritsch Bernhard , Huflage Henner
Published: July 2022

Objectives

Hardening the x-ray beam, tin prefiltration is established for imaging of high-contrast subjects in energy-integrating detector computed tomography (EID-CT). With this work, we aimed to investigate the dose-saving potential of spectral shaping via tin prefiltration in photon-counting detector CT (PCD-CT) of the temporal bone.

Methods

Deploying dose-matched scan protocols with and without tin prefiltration on a PCD-CT and EID-CT system (low-/intermediate-/full-dose: 4.8/7.6–7.7/27.0–27.1 mGy), 12 ultra-high-resolution examinations were performed on each of 5 cadaveric heads. While 120 kVp was applied for standard imaging, the protocols with spectral shaping used the highest potential available with tin prefiltration (EID-CT: Sn 150 kVp, PCD-CT: Sn 140 kVp). Contrast-to-noise ratios and dose-saving potential by spectral shaping were computed for each scanner. Three radiologists independently assessed the image quality of each examination with the intraclass correlation coefficient being computed to measure interrater agreement.

Results

Regardless of tin prefiltration, PCD-CT with low (171.2 ± 10.3 HU) and intermediate radiation dose (134.7 ± 4.5 HU) provided less image noise than full-dose EID-CT (177.0 ± 14.2 HU; P < 0.001). Targeting matched image noise to 120 kVp EID-CT, mean dose reduction of 79.3% ± 3.9% could be realized in 120 kVp PCD-CT. Subjective image quality of PCD-CT was better than of EID-CT on each dose level (P < 0.050). While no distinction was found between dose-matched PCD-CT with and without tin prefiltration (P ≥ 0.928), Sn 150 kVp EID-CT provided better image quality than 120 kVp EID-CT at high and intermediate dose levels (P > 0.050). The majority of low-dose EID-CT examinations were considered not diagnostic, whereas PCD-CT scans of the same dose level received satisfactory or better ratings. Interrater reliability was excellent (intraclass correlation coefficient 0.903).

Conclusions

PCD-CT provides superior image quality and significant dose savings compared with EID-CT for ultra-high-resolution examinations of the temporal bone. Aiming for matched image noise, high-voltage scan protocols with tin prefiltration facilitate additional dose saving in EID-CT, whereas superior inherent denoising decreases the dose reduction potential of spectral shaping in PCD-CT.
Comparison of 18F-MFBG and 68Ga-DOTATATE PET/CT in the Imaging of Metastatic Paraganglioma and Pheochromocytoma
Authors: Deng Maoxue , Shu Qiaoqiao , Hu Mei , Chen Yue , Cai Liang
Published: July 2022

Two men with metastatic paraganglioma/pheochromocytoma underwent PET/CT examination in our hospital to understand the treatment effect and progression of the disease. Both patients had previously been treated with 131I-MIBG, and at this evaluation, both of them underwent 68Ga-DOTATATE and 18F-MFBG PET/CT. The 68Ga-DOTATATE PET/CT showed more metastases in the images of these 2 patients. This case highlighted that 68Ga-DOTATATE PET/CT is superior to 18F-MFBG PET/CT in detecting metastases from paraganglioma and pheochromocytoma in these 2 patients.
Intra-articular Treatment of Digital Osteoarthritis by Radiosynoviorthesis—Clinical Outcome in Long-term Follow-up
Authors: Ehlich Hans , Kresnik Ewald , Klett Rigobert , Freudenberg Lutz S. , Kampen Willm Uwe
Published: July 2022

Osteoarthritis (OA) is a degenerative joint disease, leading to increasing pain and disability. In digital joints, OA results in a reduced quality of life with significantly restricted daily manual activities. Inflammatory processes are increasingly recognized as an important part of OA. Thus, a local anti-inflammatory treatment using intra-articularly applied radiocolloids can be used for treatment.

Purpose

This retrospective study analyzed the long-term effects of radiosynoviorthesis (RSO) with special emphasis to local joint pain in patients from 4 different RSO centers in Germany and Austria.

Methods

A total of 168 finger joints in 147 patients with digital joint OA were investigated. The indication for RSO was based on both clinical complaints and a proven synovitis, despite anti-inflammatory pharmacotherapy and previous intra-articular corticosteroid injections. Radiosynoviorthesis was performed according to international guidelines. A numeric visual analog scale (VAS) before and after treatment was used to measure the outcome. Follow-up was done for at least 2 years after treatment, in some patients even over 10 years.

Results

Radiosynoviorthesis resulted in a significant reduction of VAS values in most of the patients, lasting for the whole period of follow-up. Two-thirds of the treated joints showed clinically relevant improvement, if a reduction of 30% in VAS values was defined as a reasonable cutoff. The best results were achieved in thumb base joints.

Conclusions

This article confirms that RSO is a suitable treatment option for digital joint OA with a proven synovitis. The analgesic effect is long-lasting and comparable to the success of RSO in patients with rheumatoid arthritis.
Algae drive convergent bacterial community assembly when nutrients are scarce
Authors: Prabhakara Kaumudi H. , Kuehn Seppe
Published: July 2022

The assembly of microbial communities is a complex dynamical process that determines community structure and function. Assembly can be influenced by species-species interactions, invasions, the availability of nutrients, and microbial physiology. The interdependence of these factors presents a challenge for understanding community assembly. For example, species-species interactions can be modulated by the availability of nutrients. Here we sought to understand how nutrient supply modulated interactions to affect the assembly process. We exploited algae in association with complex bacterial consortia from soils as models for ubiquitous phototroph-heterotroph communities that play an important role in global primary production. Studying bacterial communities assembled with and without the alga in environments with varying frequency of nutrient supply allowed us to differentiate the impacts of the algae from nutrient availability on the assembly process. A statistical decomposition of community taxonomic structure revealed that it is possible to separate the effects of biotic (presence of algae) and abiotic (nutrient supply rates) factors on community assembly. We found that when the supply of external nutrients is infrequent, the algae strongly impact bacterial community assembly, driving initially diverse bacterial consortia to converge to a common structure. Analysis of sequencing data revealed that this convergence is largely mediated by algal inhibition of specific bacterial taxa. Conversely, when nutrients are supplied with high frequency, bacterial community assembly is not impacted by the presence of the alga. This study shows that complex phototroph-heterotroph communities can be powerful model systems for understanding the assembly process in a context relevant to the global ecosystem functioning.
Genomic evidence for ancient migration routes along South America’s Atlantic coast
Authors: dos Santos Andre Luiz Campelo , Owings Amanda , Lavalle Sullasi Henry Socrates , Gokcumen Omer , DeGiorgio Michael , Lindo John
Published: July 2022

An increasing body of archaeological and genomic evidence has hinted to a complex settlement process of the Americas. This is especially true for South America, where unexpected ancestral signals have raised perplexing scenarios for the early migrations into different regions of the continent. Here we present ancient genomes from the archaeologically rich Northeast Brazil and compare them to ancient and present-day genomic data. We find a distinct relationship between ancient genomes from Northeast Brazil, Lagoa Santa, Uruguay and Panama, representing evidence for ancient migration routes along South America’s Atlantic coast. To further add to the existing complexity, we also detect greater Denisovan than Neanderthal ancestry in ancient Uruguay and Panama individuals. Moreover, we find a strong Australasian signal in an ancient genome from Panama. This work sheds light on the deep demographic history of eastern South America and presents a starting point for future fine-scale investigations on the regional level.
Relaxing parametric assumptions for non-linear Mendelian randomization using a doubly-ranked stratification method
Authors: Tian Haodong , Mason Amy M. , Liu Cunhao , Burgess Stephen
Published: July 2022

Non-linear Mendelian randomization is an extension to standard Mendelian randomization to explore the shape of the causal relationship between an exposure and outcome using an instrumental variable. The approach divides the population into strata and calculates separate instrumental variable estimates in each stratum. However, the standard implementation of stratification in non-linear Mendelian randomization, referred to as the residual method, relies on strong parametric assumptions of linearity and homogeneity between the instrument and the exposure to form the strata. If these stratification assumptions are violated, the instrumental variable assumptions may be violated in the strata even if they are satisfied in the population, resulting in misleading estimates. We propose a new stratification method, referred to as the doubly-ranked method, that does not require strict parametric assumptions to create strata with different average levels of the exposure such that the instrumental variable assumptions are satisfied within the strata. Our simulation study indicates that the doubly-ranked method can obtain unbiased stratum-specific estimates and appropriate coverage rates even when the effect of the instrument on the exposure is non-linear or heterogeneous. Moreover, it can also provide unbiased estimates when the exposure is coarsened (that is, rounded, binned into categories, or truncated), a scenario that is common in applied practice and leads to substantial bias in the residual method. We applied the proposed doubly-ranked method to investigate the effect of alcohol intake on systolic blood pressure, and found evidence of a positive effect of alcohol intake, particularly at higher levels of alcohol consumption.
Nonlinear effect of light intensity on normal axial development of rhesus monkeys
Authors: Hu Ying-Zhou , Yang Hua , Wu Jing , Li Hao , Lv Long-Bao , Zhu Zhu , Zhou Lu-Yao , Zhang Yu-Hua , Yan Fang-Fang , Fan Shu-Han , Li Cheng-Yu , Wang Shu-Xiao , Zhao Jian-Ping , Qi Qiang , Huang Chang-Bing , Hu Xin-Tian
Published: July 2022

Purpose

To investigate the effects of different indoor lighting intensity (500 lx, 750 lx and 1,000 lx) on normal ocular axial length growth by using juvenal rhesus monkeys.

Methods

Twenty-four juvenile monkeys were exposed continuously to normal intensity light (NIL, 500 lx, n=16), medium intensity light (MIL, 750 lx, n=8) and high intensity light (HIL, 1 000 lx, n=8), with a same CCT value (about 3000 K) for 246 days. Axial length, anterior chamber depth, corneal curvature radius were measured at about a monthly interval.

Results

After 246 days of light exposure, the growth of axial length of the MIL group (750 lx) were 0.151 ± 0.081 mm and 0.139 ± 0.070 mm in the right and left eyes, respectively, and significantly larger in comparison with the NIL group (500lx, OD: 0.068 ± 0.055 mm, OS: 0.074 ± 0.057 mm) and the HIL group (1000lx,OD:0.063 ± 0.093 mm, OS: 0.084 ± 0.052 mm) monkeys. This effect was stable and robust during the whole experimental period.

Conclusion

The effects of different intensity lighting on normal ocular axial development was not linear as most people currently think. We must be cautious when it comes to elevate light intensity in classrooms. Whether this conclusion is correct under lights of other CCT value needs further study.
Meiotic resetting of the cellular Sod1 pool is driven by protein aggregation, degradation, and transient LUTI-mediated repression
Authors: Wende Helen M. Vander , Gopi Mounika , Onyundo Megan , Medrano Claudia , Adanlawo Temiloluwa , Brar Gloria A.
Published: July 2022

Gametogenesis requires packaging of the cellular components needed for the next generation. In budding yeast, this process includes degradation of many mitotically stable proteins, followed by their resynthesis. Here, we show that one such case—Superoxide dismutase 1 (Sod1), a protein that commonly aggregates in human ALS patients—is regulated by an integrated set of events, beginning with the formation of pre-meiotic Sod1 aggregates. This is followed by degradation of a subset of the prior Sod1 pool and clearance of Sod1 aggregates. As degradation progresses, Sod1 protein production is transiently blocked during mid-meiotic stages by transcription of an extended and poorly translated SOD1 mRNA isoform, SOD1LUTI. Expression of SOD1LUTI is induced by the Unfolded Protein Response, and it acts to repress canonical SOD1 mRNA expression. SOD1LUTI is no longer expressed following the meiotic divisions, enabling a resurgence of canonical mRNA and synthesis of new Sod1 protein such that gametes inherit a full complement of this important enzyme that is essential for gamete viability. Altogether, this work reveals meiosis to be an unusual cellular context in which Sod1 levels are tightly regulated. Our findings also suggest that further investigation of Sod1 during yeast gametogenesis could shed light on conserved aspects of its aggregation and degradation that could have implications for our understanding of human disease.
Single-Cell RNA-seq of Heart Reveals Intercellular Communication Drivers of Myocardial Fibrosis in Diabetic Mice
Authors: Li Wei , Lou Xinqi , Zha Yingjie , Zha Jun , Hong Lei , Xie Zhanli , Yang Shudi , Wang Chen , An Jianzhong , Zhang Zhenhao , Qiao Shigang
Published: July 2022

Diabetes-induced cardiomyopathy is characterized by myocardial fibrosis as a main pathology. In-depth study of cardiac heterogeneity and cell-to-cell interactions will help to reveal the pathogenesis of diabetic myocardial fibrosis and provide potential targets for the treatment of this disease. Here, we insighted into the intercellular communication drivers underlying myocardial fibrosis in mouse heart with high-fat-diet (HFD)/streptozotocin (STZ)-induced diabetes at single-cell resolution. Intercellular and protein-protein interaction networks of fibroblasts and macrophages, endothelial cells, as well as fibroblasts and epicardial cells reveal critical changes in ligand-receptor interactions such as Pdgf(s)-Pdgfra and Efemp1-Egfr, which promote the development of a profibrotic microenvironment during diabetes progression and confirm that specific inhibition of Pdgfra axis can significantly improve diabetic myocardial fibrosis. We further identified the phenotypically distinct Hrchi and Postnhi fibroblast subpopulations that are associated with pathological extracellular matrix remodeling, of which Hrchi fibroblasts are the most profibrogenic under diabetic conditions. Finally, we validated the role of Itgb1 hub gene mediated intercellular communication drivers of diabetic myocardial fibrosis in Hrchi fibroblasts, and confirmed the result by AAV9-mediated Itgb1 knockdown in the heart of diabetic mice. In summary, cardiac cell mapping provides novel insights into intercellular communication drivers underlying pathological extracellular matrix remodeling during diabetic myocardial fibrosis.
Imaginal disc growth factors areDrosophilaChitinase-like Proteins with roles in morphogenesis and CO2response
Authors: Sustar Anne , Strand Liesl , Zimmerman Sandra , Berg Celeste
Published: July 2022

Chitinase-like proteins (CLPs) are members of the family 18 glycosyl hydrolases, which include chitinases and the enzymatically inactive CLPs. A mutation in the enzyme’s catalytic site, conserved in vertebrates and invertebrates, allowed CLPs to evolve independently with functions that do not require chitinase activity. CLPs normally function during inflammatory responses, wound healing, and host defense, but when they persist at excessive levels at sites of chronic inflammation and in tissue-remodeling disorders, they correlate positively with disease progression and poor prognosis. However, little is known about their physiological function.Drosophila melanogasterhas six CLPS, termed Imaginal disc growth factors (Idgfs), encoded byIdgf1,Idgf2,Idgf3,Idgf4,Idgf5, andIdgf6. In this study we developed tools to facilitate characterization of the physiological roles of the Idgfs by deleting each of theIdgfgenes using the CRISPR/Cas9 system and assessing loss-of-function phenotypes. Using null lines, we showed that loss-of-function for all six Idgf proteins significantly lowers fertility and viability and compromises germ cell migration. We also showed that Idgfs play roles in epithelial morphogenesis, maintaining proper epithelial architecture and cell shape, regulating E-cadherin and cortical Actin, and protecting these tissues against CO2exposure. Defining the normal molecular mechanisms of CLPS is key to understanding how deviations tip the balance from a physiological to a pathological state.
Structural changes in chromosomes driven by multiple condensin motors during mitosis
Authors: Dey Atreya , Shi Guang , Takaki Ryota , Thirumalai D.
Published: July 2022

We created a computational framework that describes the loop extrusion (LE) by multiple condensin I and II motors in order to investigate the changes in chromosome organization during mitosis. The theory accurately reproduces the experimentally measured contact probability profiles for the mitotic chromosomes in HeLa and DT40 cells. The rate of loop extrusion is smaller at the start of mitosis and increases as the cells approach the metaphase. The mean loop size generated by condensin II is about six times larger than the ones created by condensin I. The loops, which overlap with each other, are stapled to a central dynamically changing helical scaffold formed by the motors during the LE process. The structures of the mitotic chromosomes, using a data-driven method that uses the Hi-C contact map as input, are best described as random helix perversion (RHP) in which the handedness changes randomly along the scaffold. The extent of propagation in the RHP structures is less in HeLa cells than in the DT40 chromosomes.
Diversity and prevalence ofClostridium innocuumin the human gut microbiota
Authors: Bhattacharjee Disha , Flores Clara , Woelfel-Monsivais Christine , Seekatz Anna M.
Published: July 2022

Clostridia are a polyphyletic group of Gram-positive, spore-forming anaerobes in the Firmicutes phylum that significantly impact metabolism and functioning of human gastrointestinal tract. Recently, Clostridia were divided into two separate classes, Clostridia and Erysipelotrichia, based on phenotypic and 16S rRNA gene-based differences. While Clostridia include many well-known pathogenic bacteria, Erysipelotrichia remain relatively uncharacterized, particularly regarding their role as a pathogen vs. commensal. Despite wide recognition as a commensal, the Erysipelotrichial species,Clostridium innocuum, has recently been associated with various disease states. To further understand the ecological and potential virulent role ofC. innocuum, we conducted a genomic comparison across 38C. innocuumisolates and 75 publicly available genomes. Based on colony morphology, we isolated multipleC. innocuumcultivars from the feces of healthy human volunteers (n=5). Comparison of the 16S rRNA gene of our isolates against publicly available microbiota datasets in healthy individuals suggests a high prevalence ofC. innocuumacross the human population (> 80%). Analysis of single nucleotide polymorphisms (SNPs) across core genes and average nucleotide identify (ANI) revealed the presence of 4 clades among all available unique genomes (n=108 total). Investigation of carbohydrate and protein utilization pathways, including comparison against the carbohydrate-activating-enzyme (CAZyme) database, demonstrated inter-and intra-clade differences that were further substantiatedin vitro. Collectively, these data indicate genetic variance within theC. innocuumspecies that may help clarify its role in human disease and health.

IMPORTANCE

Clostridia are a group of medically important anaerobes as both commensals and pathogens. Recently, a new class of Erysipelotrichia containing a number of re-assigned Clostridial species has emerged, includingClostridium innocuum. Recent studies have implicatedC. innocuumas a potential causative agent of diarrhea in patients from whomClostridioides difficilecould not be isolated. Using genomic andin vitrocomparison, this study sought to characterizeC. innocuumin the healthy human gut. Our analyses suggest thatC. innocuumis a highly prevalent and diverse species, demonstrating clade-specific differences in metabolism and potential virulence. Collectively, this study is the first investigation into a broader description ofC. innocuumas a human gut inhabitant.
Suspected Adverse Drug Reactions of the Type 2 Antidiabetic Drug Class Dipeptidyl-Peptidase IV inhibitors (DPP4i): Can polypharmacology help explain?
Authors: Jones Lauren , Jones Alan M.
Published: July 2022

To interpret the relationship between the polypharmacology of dipeptidyl-peptidase IV inhibitors (DPP4i) and their suspected adverse drug reaction (ADR) profiles using a national registry.

A retrospective investigation into the suspected ADR profile of four licensed DPP4i in the United Kingdom using the National MHRA Yellow Card Scheme and OpenPrescribing databases. Experimental data from the ChEMBL database alongside physiochemical (PC) and pharmacokinetic (PK) profiles were extracted and interpreted.

DPP4i show limited polypharmacology alongside low suspected ADR rates. We found minimal statistical difference between the unique ADR profiles ascribed to the DPP4i except for total ADRs (χ2;p<.05). Alogliptin consistently showed the highest suspected ADR rate per 1,000,000 items prescribed. Saxagliptin showed the lowest suspected ADR rate across all organ classes but did not reach statistical difference (χ2;p>.05). We also confirmed the Phase III clinical trial data that showed gastrointestinal and skin reactions are the most reported ADR across the class and postulated underlying mechanisms for this based on possible drug interactions.

We have proposed underlying mechanisms behind the reported suspected ADRs and their polypharmacology. The main pharmacological mechanism behind the ADRs is attributed to interactions with DPP4 activity and/or structure homologue (DASH) proteins which augment the immune-inflammatory modulation of DPP4.
Loss of polarity regulators initiates gasdermin E mediated pyroptosis in human maternal fetal interface trophoblasts
Authors: Patel Khushali , Nguyen Jasmine , Shaha Sumaiyah , Brightwell Amy , Duan Wendy , Zubkowski Ashley , Riddell Meghan
Published: July 2022

The syncytiotrophoblast is the placental epithelial cell that forms the maternal surface of the human placenta, acting as a barrier and facilitating exchange between mother and fetus. Syncytiotrophoblast dysfunction is a feature of pregnancy pathologies, like preeclampsia. Dysfunctional syncytiotrophoblast display a loss of microvilli, a marker of aberrant apical-basal polarization, but little data exists about the regulation of syncytiotrophoblast polarity. Atypical protein kinase-c (aPKC) isoforms are conserved polarity regulators. Thus, we hypothesized that aPKC isoforms regulate syncytiotrophoblast polarity. Using human placental explant culture and primary trophoblasts, we found that loss of aPKC activity or expression induces syncytiotrophoblast gasdermin E dependent pyroptosis. We also establish that TNF-α induces an isoform specific decrease in aPKC expression and gasdermin E dependent pyroptosis. Therefore, aPKCs are homeostatic regulators of syncytiotrophoblast function and a pathogenically relevant pro-inflammatory signal leads to a highly pro-inflammatory form of cell death at the maternal-fetal interface. Therefore, our results have important implications for the pathobiology of placental disorders.
Cholesterol-mediated tight junction formation
Authors: Shigetomi Kenta , Ikenouchi Junichi
Published: July 2022

Lipids have the ability to self-organize but the significance of this phenomenon in the assembly of membrane structures is unknown. We previously reported that cholesterol enrichment directs the formation of tight junctions (TJs), adhesion structures responsible for the epithelial barrier (Shigetomi et al., 2018). However, it is unclear how cholesterol accumulates and informs TJ formation. Cholesterol typically accumulates in the vicinity of apical cell junctions (Shigetomi et al., 2018). Surprisingly, cholesterol distribution is unaltered in an epithelial cell line that lacks TJs, generated by suppressing the expression of claudins, membrane proteins that determine the barrier properties of TJs. Assembly of claudin into hallmark ‘strands’ is canonically thought to require binding to Zonula occludens (ZO) proteins but a claudin mutant that cannot bind to ZO proteins still form strands. These results suggest a novel mechanism for TJ formation that is dependent on cholesterol and reveal an unexpected role of ZO proteins as organizers of the cholesterol domain.
Convergence of two global regulators to coordinate expression of essential virulence determinants of Mycobacterium tuberculosis
Authors: Khan Hina , Paul Partha , Sevalkar Ritesh Rajesh , Kachhap Sangita , Singh Balvinder , Sarkar Dibyendu
Published: July 2022

Cyclic AMP (cAMP) is known to function as a global regulator of M. tuberculosis gene expression. Sequence-based transcriptomic profiling identified the mycobacterial regulon controlled by the cAMP receptor protein, CRP. In this study, we identified a new subset of CRP-associated genes including virulence determinants which are also under the control of a major regulator, PhoP. Our results suggest that PhoP as a DNA binding transcription factor, impacts expression of these genes, and phosphorylated PhoP promotes CRP recruitment at the target promoters. Further, we uncover a distinct regulatory mechanism involving CRP and PhoP on transcriptional control of these genes. While both these regulators influence gene expression, we show that activation of these genes requires direct recruitment of both PhoP and CRP at their target promoters. The most fundamental biological insight is derived from the inhibition of CRP binding at the regulatory regions in a PhoP-deleted strain owing to CRP-PhoP protein-protein interactions. Based on these results, a model is proposed suggesting how CRP and PhoP function as co-activators and contribute to activation of the essential pathogenic determinants. Together, these results uncover a novel mechanism where two interacting virulence factors impact expression of virulence determinants, have significant implications on TB pathogenesis.
Elevated FOXG1 supports exit from quiescence in neural stem cells through FoxO6
Authors: Ferguson Kirsty M , Blin Carla , Garcia-Diaz Claudia , Bulstrode Harry , Bressan Raul Bardini , McCarten Katrina , Pollard Steven M.
Published: July 2022

The molecular mechanisms controlling the balance of quiescence and proliferation in adult neural stem cells (NSCs) are often deregulated in brain cancers such as glioblastoma (GBM). Previously, we reported that FOXG1, a forebrain-restricted neurodevelopmental transcription factor, is frequently upregulated in glioblastoma stem cells (GSCs) and limits the effects of cytostatic pathways, in part by repression of the tumour suppressor Foxo3. Here, we show that increased FOXG1 upregulates FoxO6, a more recently discovered FoxO family member with potential oncogenic functions. Although genetic ablation of FoxO6 in proliferating NSCs has no effect on the cell cycle or entry into quiescence, we find that FoxO6-null NSCs can no longer efficiently exit quiescence following FOXG1 elevation. Increased FoxO6 results in the formation of large acidic vacuoles, reminiscent of Pak1-regulated macropinocytosis. Consistently, Pak1 expression is upregulated by FOXG1 overexpression and downregulated upon FoxO6 loss in proliferative NSCs. These data suggest a pro-oncogenic role for FoxO6 in controlling the exit from quiescence in NSCs, and shed light on the functions of this underexplored FoxO family member.

Research highlights

FoxO6 is a downstream effector of elevated FOXG1 in mouse NSCs and GSCs.

Upregulation of FoxO6 is necessary for FOXG1 to drive efficient quiescence exit of NSCs.

FoxO6 overexpression stimulates macropinocytosis, a process regulated by the actin cytoskeleton regulator Pak1.

Pak1 is upregulated by FOXG1 overexpression and downregulated upon FoxO6 loss.
RPG interacts with E3-ligase CERBERUS to mediate rhizobial infection in Lotus japonicus
Authors: Li Xiaolin , Liu Miaoxia , Cai Min , Chiasson David , Groth Martin , Heckmann Anne B. , Wang Trevor L. , Parniske Martin , Downie J. Allan , Xie Fang
Published: July 2022

Symbiotic interactions between rhizobia and legumes result in the formation of root nodules, which fix nitrogen that can be used for plant growth. Rhizobia usually invade legume roots through a plant-made tunnel-like structure called an infection thread (IT). Rhizobium-directed polar growth (RPG) encodes a coiled-coil protein that was identified in Medicago truncatula as required for root nodule infection, but the function of RPG remains poorly understood. In this study, we identified and characterized RPG in Lotus japonicus and determined that it is required for IT formation. RPG was induced by Mesorhizobium loti or purified Nodulation factor and displayed an infection-specific expression pattern. Nodule inception (NIN) bound to the RPG promoter and induced its expression. A GFP-RPG protein was localized in puncta subcellular localization in L. japonicus root protoplasts and in root hairs infected by M. loti. The N-terminal predicted C2 lipid-binding domain of RPG was not required for this subcellular localization or for function. CERBERUS, a U-box E3 ligase which is also required for rhizobial infection, was found to be localized in similar puncta. RPG co-localized and directly interacted with CERBERUS at the early endosomes (TGN/EE) compartment and near the nuclei in root hairs after rhizobia inoculation. Our study sheds light on that a RPG-CERBERUS protein complex that is involved in an exocytotic pathway mediating IT polarity growth which is driven by nuclear migration.

One sentence summary

Puncta localization RPG-CERBERUS protein complex promote polarity growth of ITs driven by nuclear migration.
Experimental considerations for study ofC. eleganslysosomal proteins
Authors: Clancy John C. , Vo An A. , Myles Krista M. , Levenson Max T. , Ragle James Matthew , Ward Jordan D.
Published: July 2022

Lysosomes are an important organelle required for the degradation of a range of cellular components. Lysosome function is critical for development and homeostasis as dysfunction can lead to inherited genetic disorders, cancer, and neurodegenerative and metabolic disease. The acidic and protease-rich environment of lysosomes poses experimental challenges. Many fluorescent proteins are quenched or degraded, while specific red fluorescent proteins can be cleaved from translational fusion partners and accumulate. While studying MLT-11, aC. elegansmolting factor that localizes to lysosomes and the cuticle, we sought to optimize several experimental parameters. We found that, in contrast to mNeonGreen fusions, mScarlet fusions to MLT-11 missed cuticular and rectal epithelial localization. Rapid sample lysis and denaturation was critical for preventing MLT-11 fragmentation while preparing lysates for western blots. Using a model lysosomal substrate (NUC-1) we found that rigid polyproline linkers and truncated mCherry constructs do not prevent cleavage of mCherry from NUC-1. We provide evidence that extended localization in lysosomal environments prevents the detection of FLAG epitopes in western blots. Finally, we optimize an acid-tolerant green fluorescent protein (Gamillus) for use inC. elegans. These experiments provide important experimental considerations and new reagents for the study ofC. eleganslysosomal proteins.
Molecular mechanism of plasmid-borne resistance to sulfonamides
Authors: Venkatesan Meenakshi , Fruci Michael , Verellen Lou Ann , Skarina Tatiana , Mesa Nathalie , Stogios Peter J. , Savchenko Alexei
Published: July 2022

The sulfonamides (sulfas) are the oldest class of synthetic antibacterial that target the essential, conserved dihydropteroate synthase (DHPS) enzyme, encoded by folP, through chemical mimicry of its substrate p-aminobenzoic acid (pABA). Resistance has complicated their clinical utility and is widespread in pathogenic species. Resistance is mediated by acquisition of sul genes on mobile genetic elements, which code for the so-called Sul enzymes that are divergent DHPS enzymes with intrinsic sulfa-insensitivity. Even decades after the discovery of this resistance mechanism, its molecular details have not been understood. In this study, we elucidate the molecular basis for intrinsic resistance of Sul enzymes using x-ray crystallography, enzymology, mutagenesis, intrinsic tryptophan fluorescence, antibiotic susceptibility of a contemporary ΔfolP strain, and adaptive laboratory evolution of folP. We show that the active sites of Sul enzymes possess a modified pABA-interaction region based on insertion of a Phe-Gly sequence. This insertion is necessary for discrimination between pABA and sulfonamides, more than 1000-fold loss in binding affinity of sulfas to Sul enzymes, and robust pan-sulfonamide resistance. We detect no fitness cost due to this active site modification, as it does not compromise the rate of dihydropteroate biosynthesis and complements the thymidine-auxotrophy of an E. coli folP deletion strain. Lab-evolved sulfa-resistance folP recapitulated this mechanism through the same active site insertion. Finally, we show that this insertion and a nearby loop confer increased active site flexibility of Sul enzymes relative to DHPS. These results provide a molecular foundation for revisiting DHPS-targeted antibacterials to evade resistance.