bluuebunny/crossref_metadata_2025 huggingface dataset:
How Do We Define and Measure Health Equity? The State of Current Practice and Tools to Advance Health Equity
Authors: Hoyer Deborah , Dee Elizabeth , O'Leary Meghan S. , Heffernan Megan , Gelfand Katherine , Kappel Rachel , Fromknecht Catharine Q.
Published: July 2022

Introduction:

Healthy People establishes national goals and specific measurable objectives to improve the health and well-being of the nation. An overarching goal of Healthy People 2030 is to “eliminate health disparities, achieve health equity, and attain health literacy to improve the health and well-being of all.” To inform Healthy People 2030 health equity and health disparities content and products, the US Department of Health and Human Services (HHS) Office of Disease Prevention and Health Promotion (ODPHP), in collaboration with NORC at the University of Chicago, conducted a review of peer-reviewed and gray literature to examine how health equity is defined, conceptualized, and measured by public health professionals.

Methods:

We reviewed (1) peer-reviewed literature, (2) HHS and other public health organization Web sites, and (3) state and territorial health department plans. We also conducted targeted searches of the gray literature to identify tools and recommendations for measuring health equity.

Results:

While definitions of health equity identified in the scan varied, they often addressed similar concepts, including “highest level of health for all people,” “opportunity for all,” and “absence of disparities.” Measuring health equity is challenging; however, strategies to measure and track progress toward health equity have emerged. There are a range of tools and resources that have the potential to help decision makers address health equity, such as health impact assessments, community health improvement plans, and adapting a Health in All Policies approach. Tools that visualize health equity data also support data-driven decision making.

Discussion:

Using similar language when discussing health equity will help align and advance efforts to improve health and well-being for all. Healthy People objectives, measures, and targets can help public health professionals advance health equity in their work. HHS ODPHP continues to develop Healthy People tools and resources to support public health professionals as they work with cross-sector partners to achieve health equity.
Excreted 99mTc-Pertechnetate in a Renal Pelvis as a Potential False Positive in a Meckel’s Scan
Authors: Lanzo Shannon M. , Pantel Austin R. , Zhuang Hongming
Published: July 2022

A 14-year-old girl presented with right lower quadrant pain. A 99mTc-pertechnetate scan with SPECT/CT was performed to exclude a Meckel's diverticulum. The images demonstrated focal tracer uptake in the right midabdomen, which appeared early and decreased over time. However, SPECT/CT revealed that this uptake corresponded to the right renal pelvis, which was located more inferior than expected. This case emphasizes the importance of recognizing anatomic variants that may cause focal tracer uptake, as well as leveraging an understanding of tracer kinetics to inform a diagnosis.
Relating Metopic Craniosynostosis Severity to Intracranial Pressure
Authors: Blum Jessica D. , Beiriger Justin , Kalmar Christopher , Avery Robert A. , Lang Shih-Shan , Villavisanis Dillan F. , Cheung Liana , Cho Daniel Y. , Tao Wenzheng , Whitaker Ross , Bartlett Scott P. , Taylor Jesse A. , Goldstein Jesse A. , Swanson Jordan W.
Published: July 2022

Purpose:

A subset of patients with metopic craniosynostosis are noted to have elevated intracranial pressure (ICP). However, it is not known if the propensity for elevated ICP is influenced by the severity of metopic cranial dysmorphology.

Methods:

Children with nonsyndromic single-suture metopic synostosis were prospectively enrolled and underwent optical coherence tomography to measure optic nerve head morphology. Preoperative head computed tomography scans were assessed for endocranial bifrontal angle as well as scaled metopic synostosis severity score (MSS) and cranial morphology deviation score determined by CranioRate, an automated severity classifier.

Results:

Forty-seven subjects were enrolled between 2014 and 2019, at an average age of 8.5 months at preoperative computed tomography and 11.8 months at index procedure. Fourteen patients (29.7%) had elevated optical coherence tomography parameters suggestive of elevated ICP at the time of surgery. Ten patients (21.3%) had been diagnosed with developmental delay, eight of whom demonstrated elevated ICP. There were no significant associations between measures of metopic severity and ICP. Metopic synostosis severity score and endocranial bifrontal angle were inversely correlated, as expected (r=−0.545, P<0.001). A negative correlation was noted between MSS and formally diagnosed developmental delay (r=−0.387, P=0.008). Likewise, negative correlations between age at procedure and both MSS and cranial morphology deviation was observed (r=−0.573, P<0.001 and r=−0.312, P=0.025, respectively).

Conclusions:

Increased metopic severity was not associated with elevated ICP at the time of surgery. Patients who underwent later surgical correction showed milder phenotypic dysmorphology with an increased incidence of developmental delay.
Retrospective Analysis of Retroperitoneal-Abdominal-Pelvic Ganglioneuromas
Authors: Noh Sangkyu , Nessim Carolyn , Keung Emily Z. , Roland Christina L. , Strauss Dirk , Sivarajah Gausihi , Fiore Marco , Biasoni Davide , Cioffi Stefano Piero Bernardo , Mehtsun Winta , Cananzi Ferdinando Carlo Maria , Sicoli Federico , Quagliuolo Vittorio , Chen Jun , Luo Chenghua , Gladdy Rebecca A. , Swallow Carol , Johnston Wendy , Ford Samuel J. , Evenden Caroline , Tirotta Fabio , Almond Max , Nguyen Laura , Rutkowski Piotr , Krotewicz Maria , Pennacchioli Elisabetta , Cardona Kenneth , Gamboa Adriana , Hompes Daphne , Renard Marleen , Kollár Attila , Ryser Christoph O. , Vassos Nikolaos , Raut Chandrajit P. , Fairweather Mark , Krakorova Dagmar Adamkova , Quildrian Sergio , Perhavec Andraz , Nizri Eran , Farma Jeffrey M. , Greco Stephanie H. , Vincenzi Bruno , Lopez José Antonio González , Solerdecoll Mireia Solans , Iwata Shintaro , Fukushima Suguru , Kim Teresa , Tolomeo Francesco , Snow Hayden , Howlett-Jansen Ynez , Tzanis Dimitri , Nikulin Maxim , Gronchi Alessandro , Sicklick Jason K. ,   on behalf of the Transatlantic Australasian Retroperitoneal Sarcoma Working Group
Published: July 2022

Objective:

The Transatlantic Australasian Retroperitoneal Sarcoma Working Group conducted a retrospective study on the disease course and clinical management of ganglioneuromas.

Background:

Ganglioneuromas are rare tumors derived from neural crest cells. Data on these tumors remain limited to case reports and single-institution case series.

Methods:

Patients of all ages with pathologically confirmed primary retroperitoneal, intra-abdominal, and pelvic ganglioneuromas between January 1, 2000, and January 1, 2020, were included. We examined demographic, clinicopathologic, and radiologic characteristics, as well as clinical management.

Results:

Overall, 328 patients from 29 institutions were included. The median age at diagnosis was 37 years with 59.1% of patients being female. Symptomatic presentation comprised 40.9% of cases, and tumors were often located in the extra-adrenal retroperitoneum (67.1%). At baseline, the median maximum tumor diameter was 7.2 cm. One hundred sixteen (35.4%) patients underwent active surveillance, whereas 212 (64.6%) patients underwent resection with 74.5% of operative cases achieving an R0/R1 resection. Serial tumor evaluations showed that malignant transformation to neuroblastoma was rare (0.9%, N=3). Tumors undergoing surveillance had a median follow-up of 1.9 years, with 92.2% of ganglioneuromas stable in size. With a median follow-up of 3.0 years for resected tumors, 84.4% of patients were disease free after resections, whereas recurrences were observed in 4 (1.9%) patients.

Conclusions:

Most ganglioneuromas have indolent disease courses and rarely transform to neuroblastoma. Thus, active surveillance may be appropriate for benign and asymptomatic tumors particularly when the risks of surgery outweigh the benefits. For symptomatic or growing tumors, resection may be curative.
Outcome of Pancreatic Surgery During the First 6 Years of a Mandatory Audit Within the Dutch Pancreatic Cancer Group
Authors: Suurmeijer J. Annelie , Henry Anne Claire , Bonsing Bert A. , Bosscha Koop , van Dam Ronald M. , van Eijck Casper H. , Gerhards Michael F. , van der Harst Erwin , de Hingh Ignace H. , Intven Martijn P. , Kazemier Geert , Wilmink Johanna W. , Lips Daan J. , Wit Fennie , de Meijer Vincent E. , Molenaar I. Quintus , Patijn Gijs A. , van der Schelling George P. , Stommel Martijn W.J. , Busch Olivier R. , Groot Koerkamp Bas , van Santvoort Hjalmar C. , Besselink Marc G. ,   for the Dutch Pancreatic Cancer Group
Published: July 2022

Objective:

To describe outcome after pancreatic surgery in the first 6 years of a mandatory nationwide audit.

Background:

Within the Dutch Pancreatic Cancer Group, efforts have been made to improve outcome after pancreatic surgery. These include collaborative projects, clinical auditing, and implementation of an algorithm for early recognition and management of postoperative complications. However, nationwide changes in outcome over time have not yet been described.

Methods:

This nationwide cohort study included consecutive patients after pancreatoduodenectomy (PD) and distal pancreatectomy from the mandatory Dutch Pancreatic Cancer Audit (January 2014–December 2019). Patient, tumor, and treatment characteristics were compared between 3 time periods (2014–2015, 2016–2017, and 2018–2019). Short-term surgical outcome was investigated using multilevel multivariable logistic regression analyses. Primary endpoints were failure to rescue (FTR) and in-hospital mortality.

Results:

Overall, 5345 patients were included, of whom 4227 after PD and 1118 after distal pancreatectomy. After PD, FTR improved from 13% to 7.4% [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.50–0.80,P<0.001] and in-hospital mortality decreased from 4.1% to 2.4% (OR 0.68, 95% CI 0.54–0.86,P=0.001), despite operating on more patients with age >75 years (18%–22%,P=0.006), American Society of Anesthesiologists score ≥3 (19%–31%,P<0.001) and Charlson comorbidity score ≥2 (24%–34%,P<0.001). The rates of textbook outcome (57%–55%,P=0.283) and major complications remained stable (31%–33%,P=0.207), whereas complication-related intensive care admission decreased (13%–9%,P=0.002). After distal pancreatectomy, improvements in FTR from 8.8% to 5.9% (OR 0.65, 95% CI 0.30–1.37,P=0.253) and in-hospital mortality from 1.6% to 1.3% (OR 0.88, 95% CI 0.45–1.72,P=0.711) were not statistically significant.

Conclusions:

During the first 6 years of a nationwide audit, in-hospital mortality and FTR after PD improved despite operating on more high-risk patients. Several collaborative efforts may have contributed to these improvements.
Integrating large scale genetic and clinical information to predict cases of heart failure
Authors: Wu Kuan-Han H. , Wolford Brooke N. , Yu Xianshi , Douville Nicholas J. , Mathis Michael R. , Graham Sarah E. ,   Global Biobank Meta-analysis Initiative (GBMI), Surakka Ida , Hornsby Whitney E. , Bian Jiang , Zhao Lili , Willer Cristen J. , Shi Xu
Published: July 2022

Background

Heart failure (HF) is a major cause of death globally. Prediction of HF risk and early initiation of treatment could mitigate disease progression.

Objectives

The study aimed to improve the prediction accuracy of HF by integrating genome-wide association studies (GWAS)- and electronic health records (EHR)-derived risk scores.

Methods

We previously performed the largest HF GWAS to date within the Global Biobank Meta-analysis Initiative to create a polygenic risk score (PRS). To extract clinical information from high-dimensional EHR data, we treated diagnosis codes as ‘words’ and leveraged natural language processing techniques to create a clinical risk score (ClinRS). Our method first learned code co-occurrence patterns and extracted 350 latent phenotypes (low-dimensional features) representing EHR codes, then used coefficients from regression of HF on the latent phenotypes in a training set as weights to calculate patient ClinRS in a validation set. Model performances were compared between baseline (age and sex) model and models with risk scores added: 1) PRS, 2) ClinRS, and 3) PRS+ClinRS. We further compared the proposed models with Atherosclerosis Risk in Communities (ARIC) heart failure risk score.

Results

Results showed that PRS and ClinRS were each able to predict HF outcomes significantly better than the baseline model, up to eight years prior to HF diagnosis. By including both PRS and ClinRS in the model, we achieved superior performance in predicting HF up to ten years prior to HF diagnosis, two years earlier than using a single risk predictor alone. Additionally, we found that ClinRS performed significantly better than ARIC model at one year prior to disease diagnosis.

Conclusions

We demonstrate the additive power of integrating GWAS- and EHR-derived risk scores to predict HF cases prior to diagnosis.
Impact of Selection Bias on Polygenic Risk Score Estimates in Healthcare Settings
Authors: Lee Younga Heather , Thaweethai Tanayott , Sheu Yi-han , Feng Yen-Chen Anne , Karlson Elizabeth W. , Ge Tian , Kraft Peter , Smoller Jordan W.
Published: July 2022

Background

Hospital-based biobanks have become an increasingly prominent resource for evaluating the clinical impact of disease-related polygenic risk scores (PRS). However, biobank cohorts typically rely on selection of volunteers who may differ systematically from non-participants.

Methods

PRS weights for schizophrenia, bipolar disorder, and depression were derived using summary statistics from the largest available genomic studies. These PRS were then calculated in a sample of 24,153 European ancestry participants in the Mass General Brigham (MGB) Biobank. To correct for selection bias, we fitted a model with inverse probability (IP) weights estimated using 1,839 sociodemographic and clinical features extracted from electronic health records (EHRs) of eligible MGB patients. Finally, we tested the utility of a modular specification of the IP weight model for selection.

Results

Case prevalence of bipolar disorder among participants in the top decile of bipolar disorder PRS was 10.0% (95% CI: 8.8%-11.2%) in the unweighted analysis but only 6.2% (5.0%-7.5%) when selection bias was accounted for using IP weights. Similarly, case prevalence of depression among those in the top decile of depression PRS was reduced from 33.5% (31.7%-35.4%) in the unweighted analysis to 28.9% (25.8%-31.9%) after IP weighting. Modular correction for selection bias in intermediate selection steps did not substantially impact PRS effect estimates.

Conclusions

Non-random selection of participants into volunteer biobanks may induce clinically relevant selection bias that could impact implementation of PRS and risk communication in clinical practice. As efforts to integrate PRS in medical practice expand, recognition and mitigation of these biases should be considered.
Association between pregnancy and severe COVID-19 symptoms in Qatar: a cross-sectional study
Authors: Al-Qassem Alla’ K. , Humaidi Ammar B. , Al-Kuwari Amna K. , Hasan Elham M. , Yakti Nosaiba H. , Al-Hathal Rakan M. , Bansal Devendra , Abd Farag Elmoubashar Abu Baker , Al-Romaihi Hamad E. , Al-Thani Mohammed H. J. , Musa Omran A. H. , Doi Suhail , Chivese Tawanda
Published: July 2022

Background

There is inconclusive evidence whether pregnancy exacerbates COVID-19 symptoms or not, and scarce data from the Middle East and North Africa region. The aim of this study was to investigate the association between pregnancy and COVID-19 symptoms in Qatar.

Methods

This cross-sectional study was carried out using data of all women with confirmed COVID-19, comparing pregnant and non-pregnant women of child-bearing age (18-49 years). Data of all COVID-19 cases were collected by the Ministry of Public Health (MoPH) in Qatar, between March and September 2020. Symptoms were compared by pregnancy status and classified into moderate and severe. Multivariable logistic and poisson regression was carried out to investigate the association between pregnancy and severity of COVID-19 symptoms.

Results

During the study period, 105744 individuals were diagnosed with COVID-19, 16908 were women of childbearing age. From that sample, 799 women who were pregnant (mean age 29.9 years (SD 5.2)) and 16109 women who were not pregnant (mean age 33.1 years (SD 7.8)). After multivariable logistic regression, pregnancy was associated with a 1.4-fold higher odds of reporting any symptoms of COVID-19 (OR 1.41, 95% CI 1.18-1.68), and 1.3-fold higher odds of reporting shortness of breath (OR 1.29, 95% CI 1.02-1.63). After multivariable poisson regression, pregnancy was also associated with a higher number of symptoms (IRR 1.03, 95%CI 0.98-1.08).

Conclusion

Our findings suggest that, in this setting, pregnant women are more likely to have symptomatic COVID-19, and shortness of breath, compared to non-pregnant women of childbearing age.
Ocular Biometry Profile of Adult Cataract Surgery Candidates at University of Gondar, Tertiary Eye Care and Training Center, North West Ethiopia
Authors: Feleke Bemnet , Mulugeta Wossen , Wondale Teshager , Tsegaw Asamere
Published: July 2022

Background

Precise measurement of the radius of curvature [K (mm)] and axial length (AL) of the eye are vital for a good outcome of a cataract extraction surgery. Average values of these dimensions of the optical components depend on race, age and gender. Although there are a number of studies that describe these mean parameters in the Caucasian, Hispanic and Asian populations, there has been little attention given to the African population.

Objectives

The aim of this study was to estimate the biometric parameters of patients who had cataract surgery at University of Gondar (UoG), Tertiary eye care and training centre.

Materials and methods

Hospital based cross sectional study was done on patients who visited UoG Tertiary Eye Care and Training Center for cataract extraction surgery. Righton retinomax K plus 3 autorefractor,(Hutama Medical, Indonesia) and Pac Scan 300A contact A scan ultrasound, (Sonomed Escalon, NY, USA) were used to measure K (mm) and AL and calculate intraocular lens (IOL) power, respectively. Data were collected using a structured questionnaire, then entered to SPSS version 25 statistical software and analyzed.

Result

A total of 838 eyes (433 right eyes and 405 left eyes) of 486 of patients were included in this study. The mean age was 62.5 ±12.88 years. The mean K1 and K2 were 7.75±0.38 mm and 7.48±0.33 mm, respectively. The mean average of K1 and K2 (AVK) was 7.61±0.33 mm. The mean AL measured was 23.06±1.05 mm and the mean Intraocular Lens (IOL) power calculated was 21.12±2.95 D. Significant difference in mean AVK and mean AL of the eye exists between male and female patients, p value =0.000.

Conclusion

This study provides the mean values of radius of curvature of cornea, axial length of the eye and IOL power of patients who were about to undergo cataract extraction surgery at the study center. Male patients had steeper corneas and longer axial lengths than females. But age had a variable effect on both AVK and AL.
Flowering cues in a Costa Rican cloud forest: analyzing the effect of climate
Authors: Travers Steven E. , Dochtermann Ned A.
Published: July 2022

The influence of a changing climate on the phenology of organisms in a region is dependent on how regional climate cues or modifies the timing of local life history events and how those cues are changing over time. There is extensive evidence of phenolological shifts in flowering time over the past 50 years in response to increasing temperatures in temperate regions, but far less is known about tropical regions where seasonality is less temperature driven. We examined historical datasets of flowering patterns in two guilds of ornithophilous plants in the montane cloud forests of Monteverde, Costa Rica in order to identify environmental cues for flowering in nine species of plant that are important resources for hummingbirds. Bimonthly censuses of flower production were used to quantify flower production during two sampling periods:1981-1983, 1986-1991., the species studied here appear to cue flowering patterns to either accumulated drought units or a combination of accumulated drought units and chill units prior to flowering. These results have implications for how tropical cloud forest plants will respond to climate change to the extent that drought and chill patterns are changing with time.
COLLAPSE: A representation learning framework for identification and characterization of protein structural sites
Authors: Derry Alexander , Altman Russ B.
Published: July 2022

The identification and characterization of the structural sites which contribute to protein function are crucial for understanding biological mechanisms, evaluating disease risk, and developing targeted therapies. However, the quantity of known protein structures is rapidly outpacing our ability to functionally annotate them. Existing methods for function prediction either do not operate on local sites, suffer from high false positive or false negative rates, or require large site-specific training datasets, necessitating the development of new computational methods for annotating functional sites at scale. We present COLLAPSE (Compressed Latents Learned from Aligned Protein Structural Environments), a framework for learning deep representations of protein sites. COLLAPSE operates directly on the 3D positions of atoms surrounding a site and uses evolutionary relationships between homologous proteins as a self-supervision signal, enabling learned embeddings to implicitly capture structure-function relationships within each site. Our representations generalize across disparate tasks in a transfer learning context, achieving state-of-the-art performance on standardized benchmarks (protein-protein interactions and mutation stability) and on the prediction of functional sites from the Prositedatabase. We use COLLAPSE to search for similar sites across large protein datasets and to annotate proteins based on a database of known functional sites. These methods demonstrate that COLLAPSE is computationally efficient, tunable, and interpretable, providing a general-purpose platform for computational protein analysis.
Biological condensates form percolated networks with molecular motion properties distinctly different from dilute solutions
Authors: Shen Zeyu , Jia Bowen , Xu Yang , Wessén Jonas , Pal Tanmoy , Chan Hue Sun , Du Shengwang , Zhang Mingjie
Published: July 2022

Formation of membraneless organelles or biological condensates via phase separation hugely expands cellular organelle repertoire. Biological condensates are dense and viscoelastic soft matters instead of canonical dilute solutions. Unlike discoveries of numerous different biological condensates to date, mechanistic understanding of biological condensates remains scarce. In this study, we developed an adaptive single molecule imaging method that allows simultaneous tracking of individual molecules and their motion trajectories in both condensed and dilute phases of various biological condensates. The method enables quantitative measurements of phase boundary, motion behavior and speed of molecules in both condensed and dilute phases as well as the scale and speed of molecular exchanges between the two phases. Surprisingly, molecules in the condensed phase do not undergo uniform Brownian motion, but instead constantly switch between a confined state and a random motion state. The confinement is consistent with formation of large molecular networks (i.e., percolation) specifically in the condensed phase. Thus, molecules in biological condensates behave distinctly different from those in dilute solutions. This finding is of fundamental importance for understanding molecular mechanisms and cellular functions of biological condensates in general.
Genomewide identification of subtelomeric silencing factors in budding yeast
Authors: Juárez-Reyes Alejandro , Avelar-Rivas J. Abraham , Hernandez-Valdes Jhonatan A. , Hua Bo , Campos Sergio E. , González James , González Alicia , Springer Michael , Mancera Eugenio , DeLuna Alexander
Published: July 2022

Subtelomeric gene silencing is the negative transcriptional regulation of genes located close to telomeres. This phenomenon occurs in a variety of eukaryotes with salient physiological implications, such as cell adherence, virulence, immune-system escape, and aging. The process has been widely studied in the budding yeast Saccharomyces cerevisiae, where genes involved in this process have been identified mostly on a gene-by-gene basis. Here, we introduce a quantitative approach to study subtelomeric gene silencing, that couples the classical URA3 reporter with GFP monitoring, amenable to high-throughput flow cytometry analysis. This reporter was integrated into several subtelomeric loci in the genome, where it showed a gradual range of silencing effects. By crossing strains with this dual reporter at the COS12 and YFR057W subtelomeric query loci with gene-deletion mutants, we carried out a genome-wide, comprehensive screen for subtelomeric-silencing factors. The approach was replicable and allowed detection of expression changes caused by previously described silencing factors. We also identified new molecular players affecting this process, most of which are related to functions underlying chromatin conformation. This was the case of LGE1, a novel silencing factor herein reported, associated with histone ubiquitination. Our strategy can be readily combined with other reporters and gene perturbation collections, making it a versatile tool to study gene silencing at a genome-wide scale.
Three-dimensional structured illumination microscopy with enhanced axial resolution
Authors: Li Xuesong , Wu Yicong , Su Yijun , Rey-Suarez Ivan , Matthaeus Claudia , Updegrove Taylor B. , Wei Zhuang , Zhang Lixia , Sasaki Hideki , Li Yue , Guo Min , Giannini John P. , Vishwasrao Harshad D. , Chen Jiji , Lee Shih-Jong J. , Shao Lin , Liu Huafeng , Ramamurthi Kumaran S. , Taraska Justin W. , Upadhyaya Arpita , La Riviere Patrick , Shroff Hari
Published: July 2022

We present two distinct, complementary methods for improving axial resolution in three-dimensional structured illumination microscopy (3D SIM) with minimal or no modification to the optical system. First, we show that placing a mirror directly opposite the sample enables 4-beam interference with higher spatial frequency content than 3D SIM illumination, offering near-isotropic imaging with ∼120 nm lateral and 160 nm axial resolution. Second, we develop an improved deep learning method that can be directly applied to 3D SIM data, obviating the need for additional hardware. This procedure results in ∼120 nm isotropic resolution and can be combined with denoising to facilitate volumetric imaging spanning dozens of time points. We demonstrate the potential of these advances by imaging a variety of cellular samples, delineating the nanoscale distribution of vimentin and microtubule filaments, observing the relative positions of caveolar coat proteins and lysosomal markers, and visualizing rich cytoskeletal dynamics within T-cells in the early stages of immune synapse formation.
Molecular mechanism of GTP binding- and dimerization-induced enhancement of Sar1-mediated membrane remodeling
Authors: Paul Sanjoy , Audhya Anjon , Cui Qiang
Published: July 2022

The Sar1 GTPase initiates Coat Protein II (COPII)-mediated protein transport by generating membrane curvature at subdomains on the Endoplasmic Reticulum, where it is activated by the guanine nucleotide exchange factor (GEF) Sec12. Crystal structures of GDP- and GTP-bound forms of Sar1 suggest that it undergoes a conformational switch in which GTP binding enhances the exposure of an amino-terminal amphipathic helix necessary for efficient membrane penetration. However, key residues in the amino-terminus were not resolved in crystal structures, and experimental studies have suggested that the amino-terminus of Sar1 is solvent-exposed in the absence of membrane, even in the GDP-bound state. Therefore, the molecular mechanism by which GTP binding activates the membrane remodeling activity of Sar1 remains unclear. Using atomistic molecular dynamics simulations, we compare the membrane binding and curvature generation activities of Sar1 in its GDP- and GTP-bound states. We show that in the GTP-bound state, Sar1 inserts into the membrane with its complete (residues 1-23) amphipathic amino-terminal helix, while Sar1-GDP binds to the membrane only through its first 12 residues. Such differential membrane binding modes translate into significant differences in the protein volume inserted into the membrane. As a result, Sar1-GTP generates positive membrane curvature 10-20 times higher than Sar1-GDP. Dimerization of the GTP-bound form of Sar1 further amplifies curvature generation. Taken together, our results present a detailed molecular mechanism for how the nucleotide-bound state of Sar1 regulates its membrane binding and remodeling activities in a concentration dependent manner, paving the way toward a better understanding COPII-mediated membrane transport.

Significance Statement

Amphipathic helices play established roles in penetrating lipid bilayers to produce local membrane curvature. The degree of curvature generated has been suggested to depend on the penetration depth of the amphipathic helix, its amino acid sequence, and the protein volume inserted into the membrane. However, the relative contributions of each of these factors in membrane bending remain unclear. Using the Sar1 protein monomer bound to different nucleotides (GDP vs. GTP) and its GTP-bound dimeric form as examples, we explicitly show that while the precise amino acid sequence and insertion depth of the amphipathic helix are relevant, the generated membrane curvature is most correlated with the volume of protein insertion into the membrane.
Nuanced role for dendritic cell intrinsic IRE1 RNase in the regulation of antitumor adaptive immunity
Authors: Flores-Santibañez Felipe , Rennen Sofie , Fernandez Dominique , De Nolf Clint , Gaete Sandra , Fuentes Camila , Moreno Carolina , Figueroa Diego , Lladser Álvaro , Iwawaki Takao , Bono María Rosa , Janssens Sophie , Osorio Fabiola
Published: July 2022

The IRE1/XBPls axis of the unfolded protein response (UPR) plays divergent roles in dendritic cell (DC) biology in steady state versus tumor contexts. Whereas tumor associated DCs show dysfunctional IRE1/XBP1s activation that curtails their function, the homeostasis of conventional type 1 DCs (cDC1) in tissues requires intact IRE1 RNase activity. Considering that cDC1s are key orchestrators of antitumor immunity, it is relevant to understand the functional versus dysfunctional roles of IRE1/XBP1s in tumor DC subtypes. Here, we show that cDC1s constitutively activate IRE1 RNase within subcutaneous B16 melanoma and MC38 adenocarcinoma tumor models. Mice lacking XBP1s in DCs display increased melanoma tumor growth, reduced T cell effector responses and accumulation of terminal exhausted CD8+T cells. Transcriptomic studies revealed that XBP1 deficiency in tumor cDCls decreased expression of mRNAs encoding XBPls and regulated IRE1 dependent decay (RIDD) targets. Finally, we find that the dysregulated melanoma growth and impaired T cell immunity noticed in XBP1 deficient mice are attributed to RIDD induction in DCs. This work indicates that IREl RNase activity in melanoma/MC38-associated DCs fine tunes aspects of antitumor immunity independently of XBP1s, revealing a differential role for the UPR axis that depends on the DC subtype and cancer model.
Axonemal regulation by curvature explains sperm flagellar waveform modulation
Authors: Gallagher Meurig T. , Kirkman-Brown Jackson C. , Smith David J.
Published: July 2022

Flagellar motility is critical to natural and many forms of assisted reproduction. The rhythmic beating and wave propagation by the flagellum propels sperm through fluid and enables modulation between penetrative progressive motion, activated side-to-side yaw and hyperactivated movement associated with detachment from epithelial binding. These changes occur in response to the properties of the surrounding fluid environment, biochemical activation state, and physiological ligands, however a parsimonious mechanistic explanation of flagellar beat generation that can explain motility modulation is lacking. In this paper we present the Axonemal Regulation of Curvature, Hysteretic model (ARCH), a curvature control-type model based on switching of active moment by local curvature, embedded within a geometrically nonlinear elastic model of the flagellum exhibiting planar flagellar beats, together with nonlocal viscous fluid dynamics. The biophysical system is parameterised completely by four dimensionless parameter groupings. The effect of parameter variation is explored through computational simulation, revealing beat patterns that are qualitatively representative of penetrative (straight progressive), activated (highly yawing) and hyperactivated (non-progressive) modes. Analysis of the flagellar limit cycles and associated swimming velocity reveals a cusp catastrophe between progressive and non-progressive modes, and hysteresis in the response to changes in critical curvature parameter. Quantitative comparison to experimental data on human sperm exhibiting typical penetrative, activated and hyperactivated beats shows a good fit to the time-average absolute curvature profile along the flagellum, providing evidence that the model is capable of providing a framework for quantitative interpretation of imaging data.
Characterization of the immunoglobulin lambda chain locus from diverse populations reveals extensive genetic variation
Authors: Gibson William S. , Rodriguez Oscar L. , Shields Kaitlyn , Silver Catherine A. , Dorgham Abdullah , Emery Matthew , Deikus Gintaras , Sebra Robert , Eichler Evan E. , Bashir Ali , Smith Melissa L. , Watson Corey T.
Published: July 2022

Immunoglobulins (IGs), crucial components of the adaptive immune system, are encoded by three genomic loci. However, the complexity of the IG loci severely limits the effective use of short read sequencing, limiting our knowledge of population diversity in these loci. We leveraged existing long read whole-genome sequencing (WGS) data, fosmid technology, and IG targeted single-molecule, real-time (SMRT) long-read sequencing (IG-Cap) to create haplotype-resolved assemblies of the IG Lambda (IGL) locus from 6 ethnically diverse individuals. In addition, we generated 10 diploid assemblies of IGL from a diverse cohort of individuals utilizing IG-cap. From these 16 individuals, we identified significant allelic diversity, including 37 novel IGLV alleles. In addition, we observed highly elevated single nucleotide variation (SNV) in IGLV genes relative to IGL intergenic and genomic background SNV density. By comparing SNV calls between our high quality assemblies and existing short read datasets from the same individuals, we show a high propensity for false-positives in the short read datasets. Finally, for the first time, we nucleotide-resolved common 5-10 Kb duplications in the IGLC region that contain functional IGLJ and IGLC genes. Together these data represent a significant advancement in our understanding of genetic variation and population diversity in the IGL locus.
Sequence Dependent Internucleosomal Interactions Dominate Array Assembly
Authors: Wang Yaqing , Stormberg Tommy , Hashemi Mohtadin , Kolomeisky Anatoly B. , Lyubchenko Yuri L.
Published: July 2022

The organization of the nucleosome array is a critical component of the chromatin assembly into higher order structure as well as its function. Here we investigated the contribution of the DNA sequence and internucleosomal interactions to the organization of the nucleosomal arrays in compact structures using Atomic Force Microscopy. We assembled nucleosomes on DNA substrates allowing for the formation of tetranucleosomes. We found that nucleosomes are capable of forming constructs with the close positioning of nucleosomes with no discernible space between them, even in the case of assembled dinucleosomes. This morphology of the array is in contrast with that observed for arrays assembled with repeats of the nucleosome positioning motifs separated by uniform spacers. Simulated assembly of tetranucleosomes by random placement along the substrates revealed that nucleosome array compaction is promoted by the interaction of the nucleosomes. We developed a theoretical model to account for the role of DNA sequence and internucleosomal interactions in the formation of the nucleosome structures. These findings suggest that, in the chromatin assembly, the affinity of the nucleosomes to the DNA sequence and the strengths of the internucleosomal interactions are the two major factors defining the compactness of the chromatin.
Adaptive decision making depends on pupil-linked arousal in rats performing tactile discrimination tasks
Authors: Narasimhan Shreya , Schriver Brian J. , Wang Qi
Published: July 2022

Perceptual decision making is a dynamic cognitive process and is shaped by many factors, including behavioral state, reward contingency, and sensory environment. To understand the extent to which adaptive behavior in decision making is dependent upon pupil-linked arousal, we trained head-fixed rats to perform perceptual decision making tasks and systematically manipulated the probability of Go and No-go stimuli while simultaneously measuring their pupil size in the tasks. Our data demonstrated that the animals adaptively modified their behavior in response to the changes in the sensory environment. The response probability to both Go and No-go stimuli decreased as the probability of the Go stimulus being presented decreased. Analyses within the signal detection theory framework showed that while the animals’ perceptual sensitivity was invariant, their decision criterion increased as the probability of the Go stimulus decreased. Simulation results indicated that the adaptive increase in the decision criterion will increase possible water rewards during the task. Moreover, the adaptive decision making is dependent upon pupil-linked arousal as the increase in the decision criterion was the largest during low pupil-linked arousal periods. Taken together, our results demonstrated that the rats were able to adjust their decision making to maximize rewards in the tasks, and that adaptive behavior in perceptual decision making is dependent upon pupil-linked arousal.
Single Photon smFRET. II. Application to Continuous Illumination
Authors: Saurabh Ayush , Safar Matthew , Fazel Mohamadreza , Sgouralis Ioannis , Pressé Steve
Published: July 2022

Here we adapt the Bayesian nonparametrics (BNP) framework presented in the first companion manuscript to analyze kinetics from single photon, single molecule Förster Resonance Energy Transfer (smFRET) traces generated under continuous illumination. Using our sampler, BNP-FRET, we learn the escape rates and the number of system states given a photon trace. We benchmark our method by analyzing a range of synthetic and experimental data. Particularly, we apply our method to simultaneously learn the number of system states and the corresponding kinetics for intrinsically disordered proteins (IDPs) using two-color FRET under varying chemical conditions. Moreover, using synthetic data, we show that our method can deduce the number of system states even when kinetics occur at timescales of interphoton intervals.

Why It Matters

In the first companion manuscript of this series, we developed new methods to analyze noisy smFRET data. These methods eliminate the requirement ofa priorispecifying the dimensionality of the physical model describing a molecular complex’s kinetics. Here, we apply these methods to experimentally obtained datasets with samples illuminated by time-invariant laser intensities. In particular, we study interactions of IDPs.
Polymer dynamics relates chromosome mixing to temporal changes in biological contact maps
Authors: Bajpai Gaurav , Safran Samuel
Published: July 2022

Chromosomes are arranged in distinct territories within the nucleus of animal cells. Recent experiments have shown that these territories overlap at their edges, suggesting partial mixing during interphase. Genomewide, biological contact maps in humans and Drosophila show only a low degree of contact between different chromosomes; however, the mixing in yeast is considerably higher. Recent theoretical estimates considered topological mixing of chromosomes by polymer reptation, and suggested that the time scale for chromosome mixing is years. This implies that a cell will typically divide before its chromosomes mix by reptation. Here, we use a generic polymer simulation to quantify the dynamics of chromosome mixing over time. We introduce the chromosome mixing index that quantifies the mixing of distinct chromosomes in the nucleus. We find that the chromosome mixing index increases as a power-law with time, and the scaling exponent varies non-monotonically with self-interaction and volume fraction. By comparing the chromosome mixing index with both subdiffusion due to (nontopological) intermingling of chromosomes as well as longer-time reptation, we show that the scaling exponent of the chromosome mixing index is related to intermingling for relatively small chromosome attractions and to reptation for large attractions. The model is extended to realistic biological conditions.
Prospective investigation of SARS-CoV-2 seroprevalence in relation to natural infection and vaccination between October 2020 and September 2021 in the Czech Republic
Authors: Thon Vojtěch , Piler Pavel , Pavlík Tomáš , Andrýsková Lenka , Doležel Kamil , Kostka David , Pikhart Hynek , Bobák Martin , Klánová Jana
Published: July 2022

Purpose

Monitoring the seroprevalence of COVID-19 antibodies is an important tool to design and adjust preventive strategies. We used prospective data on a large population sample with repeated IgG antibody measurement to examine changes in seropositivity before and during the national vaccination campaign in the Czech Republic.

Methods

22,130 persons provided blood samples for COVID-19 IgG antibody measurement at two time points approximately 5-7 months apart, between October 2020 and March 2021 (Phase 1, before vaccination), and between April and September 2021 (during vaccination campaign).

Results

Before vaccination (Phase 1), seroprevalence increased from 15% in October 2020 to 56% in March 2021. By the end of Phase 2, in September 2021, prevalence increased to 91%; the highest seroprevalence was seen among vaccinated persons with and without previous SARS-CoV-2 infection (99.7% and 97.2%, respectively), while the lowest seroprevalence was found among unvaccinated persons with no signs of disease (26%). Vaccination rates were lower in persons who were seropositive in phase 1 but increased with age and body mass index. Only 9% of unvaccinated subjects who were seropositive in phase 1 became seronegative by phase 2.

Conclusion

The rapid increase in seropositivity during the 2nd wave of the COVID-19 epidemic (covered by phase 1 of this study) was followed by a similarly steep rise in seroprevalence during the national vaccination campaign, reaching seropositivity rates of over 97% among vaccinated persons.
The Effect of SARS-COV-2 Variant on Respiratory Features and Mortality Among Vaccinated and Non-Fully Vaccinated Patients
Authors: Hughes Thomas D. , Subramanian Ajan , Chakraborty Rana , Cotton Shannon A. , Giraldo Herrera Maria Del Pilar , Huang Yong , Lambert Natalie , Pinto Melissa D. , Rahmani Amir M. , Sierra Carmen Josefa , Downs Charles A.
Published: July 2022

Background

SARS-CoV-2 (COVID-19) has caused over 80 million infections and 973,000 deaths in the United States, and mutations are linked to increased transmissibility. This study aimed to determine the effect of SARS-CoV-2 variants on respiratory features and mortality and to determine the effect of vaccination status.

Method

A retrospective review of medical records (n=63,454 unique patients) using The University of California Health COvid Research Data Set (UC CORDS) was performed to identify respiratory features, vaccination status, and mortality. Variants were identified using the CDC data tracker.

Results

Increased odds of death were observed among those not fully vaccinated (Delta OR: 1.64, p = 0.052; Omicron OR: 1.96, p < 0.01). Later variants (i.e., Delta and Omicron) demonstrated a reduction in the frequency of lower respiratory tract features with a concomitant increase in upper respiratory tract features. Vaccination status was associated with survival and a decrease in the frequency of many upper and lower respiratory tract features.

Discussion

SARS-CoV-2 variants show a reduction in lower respiratory tract features with an increase in upper respiratory tract features. Being fully vaccinated results in fewer respiratory features and higher odds of survival, supporting vaccination in preventing morbidity and mortality from COVID-19.
Expansion microscopy of nuclear structure and dynamics in neutrophils
Authors: Holsapple Jason Scott , Schnitzler Lena , Rusch Louisa , Baldeweg Tobias Horst , Neubert Elsa , Kruss Sebastian , Erpenbeck Luise
Published: July 2022

Neutrophils are key players of the immune system and possess an arsenal of effector functions, including the ability to form and expel neutrophil extracellular traps (NETs) in a process termed NETosis. During NETosis, the nuclear DNA/chromatin expands until it fills the whole cell and is released into the extracellular space. NETs are composed of DNA decorated with histones, proteins or peptides and NETosis is implicated in many diseases. Resolving the structure and dynamics of the nucleus in great detail is essential to understand the underlying processes but so far super-resolution methods have not been applied. Here, we developed an expansion microscopy-based method and determined the spatial distribution of chromatin/DNA, histone H1, and nucleophosmin (NPM1) with a 4.9-fold improved resolution (< 40 nm) and increased information content. It allowed us to identify the punctate localization of NPM1 in the nucleus and histone-rich domains in NETotic cells with a size of 54 nm. The technique could also be applied to components of the nuclear envelope (lamins B1 and B2) and myeloperoxidase (MPO) providing a complete picture of nuclear dynamics and structure. In conclusion, expansion microscopy enables super-resolved imaging of the highly dynamic structure of nuclei in immune cells.

Why it matters

Accessibility to high-resolution imaging is critical to advancing research across various disciplines. However, conventionally this requires demanding optical hardware, special fluorophores or data analysis. Expansion microscopy is a technique adaptable to different cell and tissue types and is comparatively inexpensive and easy to perform. Applying this technique to cells and compartments such as the nucleus of immune cells that are difficult to image due to their size and morphology, yields valuable structural insights that would otherwise require more difficult super-resolution methods.