bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementation of White Analytical Chemistry–Assisted Analytical Quality by Design Approach to Green Liquid Chromatographic Method for Concomitant Analysis of Anti-Hypertensive Drugs in Human Plasma
Authors: Prajapati Pintu , Shahi Abhinandan , Acharya Aneri , Pulusu Veera Shakar , Shah Shailesh
Published: July 2023

According to current concepts of white analytical chemistry (WAC), the use of organic solvents those are teratogenic and carcinogenic must be avoided for the protection of the environment and of the analysts. This led to the development and validation of the WAC–assisted green liquid chromatographic technique (reverse-phase high-pressure liquid chromatography (RP-HPLC)) for the simultaneous analysis of anti-hypertensive drugs (azilsartan medoxomil, chlorthalidone and cilnidipine) in human plasma and their fixed-dose combinations. The analytical quality by design approach was used in conjunction with the design of experiments and chemometrics concepts to develop the method. To develop the green RP-HPLC method, critical method variables (CMVs) and critical analytical attributes were identified using the multivariate analytical tools principal component analysis and partial least square regression. Using the Box–Behnken design, the design of experiments was used for CMV optimization and response surface analysis. It was possible to explore the analytical design space for the life cycle management of the RP-HPLC method. The developed method was found to be validated following International Council for Harmonization Q2 (R1) and M10 requirements. Using the red, green and blue paradigm, the existing and proposed chromatographic methods were evaluated for their validation efficacy, greenness profile and cost-effectiveness.
Leukopenia in autosomal dominant polycystic kidney disease: a single-center cohort of kidney transplant candidates with post-transplantation follow-up
Authors: Schellekens Pieter , Van Loon Elisabet , Coemans Maarten , Meyts Isabelle , Vennekens Rudi , Kuypers Dirk , Mekahli Djalila , Bammens Bert
Published: July 2023

Background

Autosomal dominant polycystic kidney disease (ADPKD) has occasionally been associated with lower peripheral white blood cell (WBC) counts. This study aimed to investigate the peripheral blood cell counts in a large cohort of kidney transplant recipients before and after kidney transplantation and its potential impact on post-transplant outcomes.

Methods

This was a retrospective study with long-term follow-up data of 2090 patients who underwent a first kidney transplantation in the Leuven University Hospitals, of whom 392 had ADPKD.

Results

In total, 2090 patients who underwent a first kidney transplantation in the Leuven University Hospitals were included, of whom 392 had ADPKD. Both pre- and post-transplantation, ADPKD patients had significantly lower total WBC counts, and more specifically lower neutrophil, lymphocyte and eosinophil counts compared with the non-ADPKD patients. This observation was independent of potential confounders such as level of inflammation, smoking habit, vitamins and pre-transplant medication. Overall survival and kidney transplant survival were significantly better in ADPKD vs non-ADPKD transplant recipients and a longer time to first infection was observed. However, no association between blood cell counts and outcome differences was found.

Conclusions

In conclusion, this large single-center study reports a strong and independent association between ADPKD and lower peripheral WBC counts both before and after kidney transplantation. Considering the role of inflammation in disease progression, further investigation into the role of WBC in ADPKD is needed.
Women with PCOS have an increased risk for cardiovascular disease regardless of diagnostic criteria—a prospective population-based cohort study
Authors: Ollila Meri-Maija , Arffman Riikka K , Korhonen Elisa , Morin-Papunen Laure , Franks Stephen , Junttila Juhani , Piltonen Terhi T
Published: July 2023

Objective

Polycystic ovary syndrome (PCOS) is associated with many cardiovascular disease (CVD) risk factors, such as obesity, type 2 diabetes mellitus and hypertension. However, it remains debatable whether the presence of multiple CVD risk factors translates to increased CVD events.

Design

A prospective, population-based Northern Finland Birth Cohort 1966.

Methods

Individuals with an expected date of birth in 1966 in Northern Finland have been followed from birth. Women in the cohort were classified as having PCOS according to either the National Institute of Health (NIH) criteria (n = 144) or the Rotterdam criteria (n = 386) at age 31, and they were compared to women without any PCOS features. The study population was re-examined at age 46, and the incidence of major adverse cardiovascular events (MACE), including myocardial infarction (MI), stroke, heart failure and cardiovascular mortality, was recorded up to age 53.

Results

During the 22-year follow-up, both women with NIH-PCOS and women with Rotterdam-PCOS had a significantly higher risk for cardiovascular events than control women. The BMI-adjusted hazard ratio (HR) for MACE in the Rotterdam-PCOS group and the NIH-PCOS group was 2.33 (1.26-4.30) and 2.47 (1.18-5.17), respectively. The cumulative hazard curves in both diagnostic categories began to diverge at age 35. Regarding the individual CVD endpoints, MI was significantly more prevalent in both women with NIH-PCOS (P = .010) and women with Rotterdam-PCOS (P = .019), when compared to control women.

Conclusions

PCOS should be considered a significant risk factor for CVD. Future follow-up will show how the risk of CVD events develops after menopausal age.
Immunotherapies for the prevention and treatment of Staphylococcus aureus infections: updates and challenges
Authors: Chung Pooi Yin
Published: July 2023

Staphylococcus aureus is the leading cause of hospital-acquired infections and can cause a wide range of diseases from mild skin infections to invasive diseases including deep surgical site infections, life-threatening bacteremia, and sepsis. This pathogen remains a challenge to manage due to its ability to rapidly develop resistance to antibiotic treatment and to form biofilms. Despite the current infection control measures which involve mainly antibiotics, the burden of infection remains high. The ‘omics’ approaches have not led to the discovery of novel antibacterials at a pace sufficient to cope with the emergence of multidrug-resistant and biofilm-forming S. aureus, Hence, new strategies for anti-infective therapies need to be explored urgently. One promising strategy is harnessing the immune response to enhance the protective antimicrobial immunity in the host. This review discusses the potential of monoclonal antibodies and vaccines as alternatives to treat and manage infections caused by planktonic and biofilms of S. aureus.
Leveraging the genetic correlation between traits improves the detection of epistasis in genome-wide association studies
Authors: Stamp Julian , DenAdel Alan , Weinreich Daniel , Crawford Lorin
Published: July 2023

Epistasis, commonly defined as the interaction between genetic loci, is known to play an important role in the phenotypic variation of complex traits. As a result, many statistical methods have been developed to identify genetic variants that are involved in epistasis, and nearly all of these approaches carry out this task by focusing on analyzing one trait at a time. Previous studies have shown that jointly modeling multiple phenotypes can often dramatically increase statistical power for association mapping. In this study, we present the “multivariate MArginal ePIstasis Test” (mvMAPIT)—a multioutcome generalization of a recently proposed epistatic detection method which seeks to detect marginal epistasis or the combined pairwise interaction effects between a given variant and all other variants. By searching for marginal epistatic effects, one can identify genetic variants that are involved in epistasis without the need to identify the exact partners with which the variants interact—thus, potentially alleviating much of the statistical and computational burden associated with conventional explicit search-based methods. Our proposed mvMAPIT builds upon this strategy by taking advantage of correlation structure between traits to improve the identification of variants involved in epistasis. We formulate mvMAPIT as a multivariate linear mixed model and develop a multitrait variance component estimation algorithm for efficient parameter inference and P-value computation. Together with reasonable model approximations, our proposed approach is scalable to moderately sized genome-wide association studies. With simulations, we illustrate the benefits of mvMAPIT over univariate (or single-trait) epistatic mapping strategies. We also apply mvMAPIT framework to protein sequence data from two broadly neutralizing anti-influenza antibodies and approximately 2,000 heterogeneous stock of mice from the Wellcome Trust Centre for Human Genetics. The mvMAPIT R package can be downloaded at https://github.com/lcrawlab/mvMAPIT.
Multiple p38/JNK mitogen-activated protein kinase (MAPK) signaling pathways mediate salt chemotaxis learning in C. elegans
Authors: Huang Taoruo , Suzuki Kota , Kunitomo Hirofumi , Tomioka Masahiro , Iino Yuichi
Published: July 2023

Animals are able to adapt their behaviors to the environment. In order to achieve this, the nervous system plays integrative roles, such as perception of external signals, sensory processing, and behavioral regulations via various signal transduction pathways. Here genetic analyses of Caenorhabditis elegans (C. elegans) found that mutants of components of JNK and p38 mitogen-activated protein kinase (MAPK) signaling pathways, also known as stress-activated protein kinase (SAPK) signaling pathways, exhibit various types of defects in the learning of salt chemotaxis. C. elegans homologs of JNK MAPKKK and MAPKK, MLK-1 and MEK-1, respectively, are required for avoidance of salt concentrations experienced during starvation. In contrast, homologs of p38 MAPKKK and MAPKK, NSY-1 and SEK-1, respectively, are required for high-salt chemotaxis after conditioning. Genetic interaction analyses suggest that a JNK family MAPK, KGB-1, functions downstream of both signaling pathways to regulate salt chemotaxis learning. Furthermore, we found that the NSY-1/SEK-1 pathway functions in sensory neurons, ASH, ADF, and ASER, to regulate the learned high-salt chemotaxis. A neuropeptide, NLP-3, expressed in ASH, ADF, and ASER neurons, and a neuropeptide receptor, NPR-15, expressed in AIA interneurons that receive synaptic input from these sensory neurons, function in the same genetic pathway as NSY-1/SEK-1 signaling. These findings suggest that this MAPK pathway may affect neuropeptide signaling between sensory neurons and interneurons, thus promoting high-salt chemotaxis after conditioning.
Hypoxanthine Induces Signs of Bladder Aging With Voiding Dysfunction and Lower Urinary Tract Remodeling
Authors: Birder Lori A , Wolf-Johnston Amanda S , Zabbarova Irina , Ikeda Youko , Robertson Anne M , Cardozo Ricardo , Azari Fatemeh , Kanai Anthony J , Kuchel George A , Jackson Edwin K
Published: July 2023

Background

Lower urinary tract syndrome (LUTS) is a group of urinary tract symptoms and signs that can include urinary incontinence. Advancing age is a major risk factor for LUTS; however, the underlying biochemical mechanisms of age-related LUTS remain unknown. Hypoxanthine (HX) is a purine metabolite associated with generation of tissue-damaging reactive oxygen species (ROS). This study tested the hypothesis that exposure of the adult bladder to HX–ROS over time damages key LUT elements, mimicking qualitatively some of the changes observed with aging.

Methods

Adult 3-month-old female Fischer 344 rats were treated with vehicle or HX (10 mg/kg/day; 3 weeks) administered in drinking water. Targeted purine metabolomics and molecular approaches were used to assess purine metabolites and biomarkers for oxidative stress and cellular damage. Biomechanical approaches assessed LUT structure and measurements of LUT function (using custom-metabolic cages and cystometry) were also employed.

Results

HX exposure increased biomarkers indicative of oxidative stress, pathophysiological ROS production, and depletion of cellular energy with declines in NAD+ levels. Moreover, HX treatment caused bladder remodeling and decreased the intercontraction interval and leak point pressure (surrogate measure to assess stress urinary incontinence).

Conclusions

These studies provide evidence that in adult rats chronic exposure to HX causes changes in voiding behavior and in bladder structure resembling alterations observed with aging. These results suggest that increased levels of uro-damaging HX were associated with ROS/oxidative stress-associated cellular damage, which may be central to age-associated development of LUTS, opening up potential opportunities for geroscience-guided interventions.
The genesis of the PM-JAY health insurance scheme in India: technical and political elements influencing a national reform towards universal health coverage
Authors: Srivastava S , Bertone M P , Parmar D , Walsh C , De Allegri M
Published: July 2023

Many countries are using health insurance to advance progress towards universal health coverage (UHC). India launched the Pradhan Mantri Jan Arogya Yojana (PM-JAY) health insurance scheme in 2018. We examine the political economy context around PM-JAY policy formulation, by examining the perspectives of policy stakeholders shaping decisions around the reform. More specifically, we focus on early policy design at the central (national) level. We use a framework on the politics of UHC reform proposed by Fox and Reich (The politics of universal health coverage in low- and middle-income countries: A framework for evaluation and action. J. Health Polit. Policy Law 2015;40:1023–1060), to categorize the reform into phases and examine the interactions between actors, institutions, interests, ideas and ideology which shaped reform decisions. We interviewed 15 respondents in Delhi between February and April 2019, who were either closely associated with the reform process or subject experts. The ruling centre-right government introduced PM-JAY shortly before national elections, drawing upon policy legacies from prior and state insurance schemes. Empowered policy entrepreneurs within the government focused discourse around ideas of UHC and strategic purchasing, and engaged in institution building leading to the creation of the National Health Authority and State Health Agencies through policy directives, thereby expanding state infrastructural and institutional power for insurance implementation. Indian state inputs were incorporated in scheme design features like mode of implementation, benefit package and provider network, while features like the coverage amount, portability of benefits and branding strategy were more centrally driven. These balanced negotiations opened up political space for a cohesive, central narrative of the reform and facilitated adoption. Our analysis shows that the PM-JAY reform focused on bureaucratic rather than ideological elements and that technical compromises and adjustments accommodating the interests of states enabled the political success of policy formulation. Appreciating these politics, power and structural issues shaping PM-JAY institutional design will be important to understand how PM-JAY is implemented and how it advances UHC in India.
Bloc Politics at the UN: How Other States Behave When the United States and China–Russia Disagree
Authors: Nurullayev Dmitriy , Papa Mihaela
Published: July 2023

China and Russia have been progressively deepening their partnership in global governance to achieve common goals. However, do other states share their policy positions? Existing scholarship addresses the dyadic affinity among major powers and the growing importance of rising power groups, but it does not examine how the policy positions of other states align with those of the United States and its major rivals: China and Russia. To investigate how states align with the positions of these major powers, we examine voting patterns in the UN General Assembly over a 30-year period from 1991 to 2020. By utilizing simple t-tests and estimating both OLS and LOGIT models (N = 219,625), we find that the Sino–Russian positions enjoy much broader global support than those of the United States. Additionally, states that belong to the Group of 77 (G-77) and soft-balancing institutions such as the Shanghai Cooperation Organization and BRICS (Brazil, Russia, India, China, and South Africa) are more likely to align with China and Russia than states that do not belong to these groups. Conversely, members of NATO are more likely to side with the United States than their non-NATO counterparts. Further, the findings suggest that the effect of states’ membership in soft-balancing institutions on their propensity to align with China and Russia has steadily increased over time. Meanwhile, the effect of states’ membership in NATO on their likelihood to align with the United States lacks a clear temporal trajectory.
UCE phylogenomics, biogeography, and classification of long-horned bees (Hymenoptera: Apidae: Eucerini), with insights on using specimens with extremely degraded DNA
Authors: Freitas Felipe V , Branstetter Michael G , Franceschini-Santos Vinícius H , Dorchin Achik , Wright Karen W , López-Uribe Margarita M , Griswold Terry , Silveira Fernando A , Almeida Eduardo A B
Published: July 2023

Long-horned bees (Apidae, Eucerini) are found in different biomes worldwide and include some important crop pollinators. In the Western Hemisphere, Eucerini received extensive taxonomic study during the twentieth century, resulting in several revisions of its genera. In contrast, progress on eucerine phylogenetic research and the genus-level classification has been slow, primarily due to the relatively homogeneous external morphology within the tribe and the rarity of many of its species in collections. Here, we present a comprehensive phylogenetic study of Eucerini based on ultraconserved elements, including 153 species from nearly all genera and subgenera and from all biogeographic regions where they occur. Many of these specimens are from museums and were collected as far back as 1909. We discuss the challenges of working with specimens with highly degraded DNA, present insights into improving phylogenetic results for both species-tree and concatenation approaches, and present a new pipeline for UCE curation (Curation of UltraconseRved Elements—CURE). Our results show the existence of seven main lineages in Eucerini and most of the genera and subgenera to be reciprocally monophyletic. Using a comprehensive and up-to-date phylogenetic framework, we: (1) propose taxonomic changes, including a new subtribal classification and reorganized generic and subgeneric limits; (2) estimate divergence times; and (3) conduct a detailed exploration of historical biogeography of long-horned bees. We find that eucerine lineages expanded their range onto most continents only after their initial diversification in southern South America during the Eocene.
Molnupiravir for the treatment of non-severe COVID-19: a systematic review and meta-analysis of 14 randomized trials with 34 570 patients
Authors: Sun Mingyao , Lai Honghao , Huang Jiajie , Liu Jianing , Li Ying , Tian Jinhui , Zhang Caiyun , Estill Janne , Zhang Zhigang , Ge Long
Published: July 2023

Background

Molnupiravir has been considered a promising candidate for COVID-19. Its efficacy and safety in non-severe COVID-19 patients and the differences between patients with different risk factors need further evaluation.

Methods

We conducted a systematic review and meta-analysis of randomized controlled trials that allocated adult patients with non-severe COVID-19 to molnupiravir or a control. We used random-effects models, and conducted subgroup analyses and meta-regression for COVID-19 patients with high-risk factors. The GRADE approach was used to rate the certainty of evidence.

Results

Fourteen trials with 34 570 patients were included. Moderate- to low-certainty evidence showed that molnupiravir was associated with a reduction in the risk of hospitalization (relative risk [RR] = 0.63, 95% CI: 0.47–0.85), risk of mechanical ventilation (RR = 0.37, 95% CI: 0.19–0.72) and time to symptom resolution (mean differences [MD] = −2.91 days, 95% CI: −3.66 to −2.16). However, no significant differences were found in adverse events, all-cause mortality, rate of and time to viral clearance, or duration of hospitalization. For the rate of viral clearance, subgroup effects were found between trials with low and high risk of bias (P = 0.001) and between trials with male or female majority (P < 0.001). For admission to hospital, subgroup effects were also found between trials with ≥50% and <50% of the participants being female (P = 0.04). Meta-regression showed a significant association between higher trial mean age and elevated risk of hospitalization (P = 0.011), and female majority and elevated risk of hospitalization (P = 0.011).

Conclusions

Molnupiravir was found to be effective in non-severe COVID-19, but the efficacy varied with age and sex.
Predicting emergency department visits and hospitalizations for patients with heart failure in home healthcare using a time series risk model
Authors: Chae Sena , Davoudi Anahita , Song Jiyoun , Evans Lauren , Hobensack Mollie , Bowles Kathryn H , McDonald Margaret V , Barrón Yolanda , Rossetti Sarah Collins , Cato Kenrick , Sridharan Sridevi , Topaz Maxim
Published: July 2023

Objectives

Little is known about proactive risk assessment concerning emergency department (ED) visits and hospitalizations in patients with heart failure (HF) who receive home healthcare (HHC) services. This study developed a time series risk model for predicting ED visits and hospitalizations in patients with HF using longitudinal electronic health record data. We also explored which data sources yield the best-performing models over various time windows.

Materials and Methods

We used data collected from 9362 patients from a large HHC agency. We iteratively developed risk models using both structured (eg, standard assessment tools, vital signs, visit characteristics) and unstructured data (eg, clinical notes). Seven specific sets of variables included: (1) the Outcome and Assessment Information Set, (2) vital signs, (3) visit characteristics, (4) rule-based natural language processing-derived variables, (5) term frequency-inverse document frequency variables, (6) Bio-Clinical Bidirectional Encoder Representations from Transformers variables, and (7) topic modeling. Risk models were developed for 18 time windows (1–15, 30, 45, and 60 days) before an ED visit or hospitalization. Risk prediction performances were compared using recall, precision, accuracy, F1, and area under the receiver operating curve (AUC).

Results

The best-performing model was built using a combination of all 7 sets of variables and the time window of 4 days before an ED visit or hospitalization (AUC = 0.89 and F1 = 0.69).

Discussion and Conclusion

This prediction model suggests that HHC clinicians can identify patients with HF at risk for visiting the ED or hospitalization within 4 days before the event, allowing for earlier targeted interventions.
COVID exacerbated the gender disparity in physician electronic health record inbox burden
Authors: Rotenstein Lisa , Jay Holmgren A
Published: July 2023

The COVID-19 pandemic was associated with significant changes to the delivery of ambulatory care, including a dramatic increase in patient messages to physicians. While asynchronous messaging is a valuable communication modality for patients, a greater volume of patient messages is associated with burnout and decreased well-being for physicians. Given that women physicians experienced greater electronic health record (EHR) burden and received more patient messages pre-pandemic, there is concern that COVID may have exacerbated this disparity. Using EHR audit log data of ambulatory physicians at an academic medical center, we used a difference-in-differences framework to evaluate the impact of the pandemic on patient message volume and compare differences between men and women physicians. We found patient message volume increased post-COVID for all physicians, and women physicians saw an additional increase compared to men. Our results contribute to the growing evidence of different communication expectations for women physicians that contribute to the gender disparity in EHR burden.
Usability and acceptability of virtual reality for chronic pain management among diverse patients in a safety-net setting: a qualitative analysis
Authors: Dy Marika , Olazo Kristan , Lyles Courtney R , Lisker Sarah , Weinberg Jessica , Lee Christine , Tarver Michelle E , Saha Anindita , Kontson Kimberly , Araojo Richardae , Brown Ellenor , Sarkar Urmimala
Published: July 2023

Objective

The aim of this study was to understand the usability and acceptability of virtual reality (VR) among a racially and ethnically diverse group of patients who experience chronic pain.

Materials and Methods

Using the Technology Acceptance Model theory, we conducted semistructured interviews and direct observation of VR use with English-speaking patients who experience chronic pain treated in a public healthcare system (n = 15), using a commercially available VR technology platform. Interviews included questions about current pain management strategies, technology use, experiences and opinions with VR, and motivators for future use.

Results

Before the study, none of the 15 participants had heard about or used VR for pain management. Common motivators for VR use included a previous history of substance use and having exhausted many other options to manage their pain and curiosity. Most participants had a positive experience with VR and 47% found that the VR modules distracted them from their pain. When attempting the navigation-based usability tasks, most participants (73%–92%) were able to complete them independently.

Discussion

VR is a usable tool for diverse patients with chronic pain. Our findings suggest that the usability of VR is not a barrier and perhaps a focus on improving the accessibility of VR in safety-net settings is needed to reduce disparities in health technology use.

Conclusions

The usability and acceptability of VR are rarely studied in diverse patient populations. We found that participants had a positive experience using VR, showed interest in future use, and would recommend VR to family and friends.
Berth allocation and scheduling at marine container terminals: A state-of-the-art review of solution approaches and relevant scheduling attributes
Authors: Li Bokang , Elmi Zeinab , Manske Ashley , Jacobs Edwina , Lau Yui-yip , Chen Qiong , Dulebenets Maxim A
Published: July 2023

Marine container terminals play a significant role for international trade networks and global market. To cope with the rapid and steady growth of the seaborne trade market, marine container terminal operators must address the operational challenges with appropriate analytical methods to meet the needs of the market. The berth allocation and scheduling problem is one of the important decisions faced by operators during operations planning. The optimization of a berth schedule is strongly associated with the allocation of spatial and temporal resources. An optimal and robust berth schedule remarkably improves the productivity and competitiveness of a seaport. A significant number of berth allocation and scheduling studies have been conducted over the last years. Thus, there is an existing need for a comprehensive and critical literature survey to analyze the state-of-the-art research progress, developing tendencies, current shortcomings, and potential future research directions. Therefore, this study thoroughly selected scientific manuscripts dedicated to the berth allocation and scheduling problem. The identified studies were categorized based on spatial attributes, including discrete, continuous, and hybrid berth allocation and scheduling problems. A detailed review was performed for the identified study categories. A representative mathematical formulation for each category was presented along with a detailed summary of various considerations and characteristics of every study. A specific emphasis was given to the solution methods adopted. The current research shortcomings and important research needs were outlined based on the review of the state-of-the-art. This study was conducted with the expectation of assisting the scientific community and relevant stakeholders with berth allocation and scheduling.
Numerical investigation of particles flow pattern and pressure distribution of coal bunker
Authors: Zhu Defu , Ji Xingwang , Huo Yuming , Wang Zhonglun , Yu Biaobiao , Wang Deyu
Published: July 2023

The stable loading and operation of a coal bunker is critical for efficient production. In this study, the coal particle contact parameters were calibrated based on the angle of repose characteristics. The loading and discharging process of the coal bunker was simulated using the EDEM program. In addition, the flow pattern of the coal particles and the distribution characteristics of the wall pressure were investigated. The results indicate that the coal particles in the bunker can be divided into two flow patterns: mass flow and funnel flow. During discharging, the wall pressure fluctuated and exhibited a local over-pressure phenomenon, with a maximum pressure coefficient of 1.75. Finally, this study provides a reasonable explanation for the transformation of the flow pattern of coal particles and the distribution characteristics of wall pressure based on the mechanism of pressure arch influence. The findings of this study can provide theoretical guidance for designing coal bunker structures.
Human neutrophil Fc gamma receptors: different buttons for different responses
Authors: Alemán Omar Rafael , Rosales Carlos
Published: July 2023

Neutrophils are fundamental cells in host defense. These leukocytes are quickly recruited from the blood to sites of infection or tissue damage. At these sites, neutrophils initiate several innate immune responses, including phagocytosis, production of reactive oxygen species, degranulation to release proteases and other antimicrobial compounds, production of inflammatory mediators, and formation of neutrophil extracellular traps. In addition to their role in innate immunity, neutrophils are now recognized as cells that also regulate adaptive immunity, via interaction with dendritic cells and lymphocytes. Neutrophils also respond to adaptive immunity by interacting with antibody molecules. Indeed, antibody molecules allow neutrophils to have antigen-specific responses. Neutrophils express different receptors for antibodies. The receptors for immunoglobulin G molecules are known as Fcγ receptors. Upon Fcγ receptor aggregation on the cell membrane, these receptors trigger distinct signal transduction cascades that activate particular cellular responses. In this review, we describe the major Fcγ receptors expressed on human neutrophils and discuss how each Fcγ receptor activates a choice of signaling pathways to stimulate particular neutrophil responses.
A Comparison of Solidification Structures and Submicroscale Cellular Segregation in Rapidly Solidified Stainless Steels Produced via Two-Piston Splat Quenching and Laser Powder Bed Fusion
Authors: Hasenbusch Zachary Arthur , Deal Andrew , Brown Ben , Wilson Davis , Nastac Laurentiu , Brewer Luke N
Published: July 2023

Fusion-based additive manufacturing techniques leverage rapid solidification (RS) conditions to create parts with complex geometries, unique microscale/nanoscale morphological features, and elemental segregation. Three custom composition stainless steel alloys with varying chromium equivalence to nickel equivalence ratio (Creq/Nieq) between 1.53 and 1.95 were processed using laser powder bed fusion (LPBF) and/or two-piston splat quenching (SQ) to produce solidification rates estimated between 0.4 and 0.8 m/s. Both scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were utilized to collect high-resolution images, electron backscatter diffraction (EBSD) phase identification, and measure cellular segregation. Similar features were observed in both LPBF and SQ samples including phase and microstructure, nanoscale oxide particles, cell size, and segregation behavior. However, dislocation pileup was observed along the cell boundaries only in the LPBF austenite solidified microstructure. Targeted adjustment of the SQ feedstock Cr and Ni concentrations, within the ASTM A240 specification for 316L resulted in no observable impact on the cell size, oxide particle size, or magnitude of segregation. Also, the amount of Ni segregation in the ferrite solidified microstructures did not significantly differ, regardless of Cr/Nieq or processing technique. SQ is demonstrated as capable of simulating RS rates and microstructures similar to LPBF for use as an alternative screening tool for new RS alloy compositions.
Resolution of Virtual Depth Sectioning from Four-Dimensional Scanning Transmission Electron Microscopy
Authors: Terzoudis-Lumsden E W C , Petersen T C , Brown H G , Pelz P M , Ophus C , Findlay S D
Published: July 2023

One approach to three-dimensional structure determination using the wealth of scattering data in four-dimensional (4D) scanning transmission electron microscopy (STEM) is the parallax method proposed by Ophus et al. (2019. Advanced phase reconstruction methods enabled by 4D scanning transmission electron microscopy, Microsc Microanal25, 10–11), which determines the scattering matrix and uses it to synthesize a virtual depth-sectioning reconstruction of the sample structure. Drawing on an equivalence with a hypothetical confocal imaging mode, we derive contrast transfer and point spread functions for this parallax method applied to weakly scattering objects, showing them identical to earlier depth-sectioning STEM modes when only bright field signal is used, but that improved depth resolution is possible if dark field signal can be used. Through a simulation-based study of doped Si, we show that this depth resolution is preserved for thicker samples, explore the impact of shot noise on the parallax reconstructions, discuss challenges to making use of dark field signal, and identify cases where the interpretation of the parallax reconstruction breaks down.
Cosmological covariance of fast radio burst dispersions
Authors: Reischke Robert , Hagstotz Steffen
Published: July 2023

The dispersion of fast radio bursts (FRBs) is a measure of the large-scale electron distribution. It enables measurements of cosmological parameters, especially of the expansion rate and the cosmic baryon fraction. The number of events is expected to increase dramatically over the coming years, and of particular interest are bursts with identified host galaxy and therefore redshift information. In this paper, we explore the covariance matrix of the dispersion measure (DM) of FRBs induced by the large-scale structure, as bursts from a similar direction on the sky are correlated by long-wavelength modes of the electron distribution. We derive analytical expressions for the covariance matrix and examine the impact on parameter estimation from the FRB DM–redshift relation. The covariance also contains additional information that is missed by analysing the events individually. For future samples containing over ∼300 FRBs with host identification over the full sky, the covariance needs to be taken into account for unbiased inference, and the effect increases dramatically for smaller patches of the sky. Also, forecasts must consider these effects as they would yield too optimistic parameter constraints. Our procedure can also be applied to the DM of the afterglow of gamma-ray bursts.
KURVS: the outer rotation curve shapes and dark matter fractions of z ∼ 1.5 star-forming galaxies
Authors: Puglisi Annagrazia , Dudzevičiūtė Ugnė , Swinbank Mark , Gillman Steven , Tiley Alfred L , Bower Richard G , Cirasuolo Michele , Cortese Luca , Glazebrook Karl , Harrison Chris , Ibar Edo , Molina Juan , Obreschkow Danail , Oman Kyle A , Schaller Matthieu , Shankar Francesco , Sharples Ray M
Published: July 2023

We present first results from the KMOS Ultra-deep Rotation Velocity Survey (KURVS), aimed at studying the outer rotation curves shape and dark matter content of 22 star-forming galaxies at z ∼ 1.5. These galaxies represent ‘typical’ star-forming discs at z ∼ 1.5, being located within the star-forming main sequence and stellar mass-size relation with stellar masses 9.5 ≤ log(M⋆/M⊙) ≤ 11.5. We use the spatially resolved H α emission to extract individual rotation curves out to 4 times the effective radius, on average, or ∼10–15 kpc. Most rotation curves are flat or rising between three and six disc scale radii. Only three objects with dispersion-dominated dynamics (vrot/σ0 ∼ 0.2) have declining outer rotation curves at more than 5σ significance. After accounting for seeing and pressure support, the nine rotation-dominated discs with vrot/σ0 ≥ 1.5 have average dark matter fractions of $50 \pm 20{{\ \rm per\ cent}}$ at the effective radius, similar to local discs. Together with previous observations of star-forming galaxies at cosmic noon, our measurements suggest a trend of declining dark matter fraction with increasing stellar mass and stellar mass surface density at the effective radius. Measurements of simulated EAGLE galaxies are in quantitative agreement with observations up to log$(M_{\star } R_{\rm eff}^{-2} /\mathrm{M_{\odot } kpc^{-2}}) \sim 9.2$, and overpredict the dark matter fraction of galaxies with higher mass surface densities by a factor of ∼3. We conclude that the dynamics of typical rotationally-supported discs at z ∼ 1.5 is dominated by dark matter from effective radius scales, in broad agreement with cosmological models. The tension with observations at high stellar mass surface density suggests that the prescriptions for baryonic processes occurring in the most massive galaxies (such as bulge growth and quenching) need to be reassessed.
LISA constraints on an intermediate-mass black hole in the Galactic Centre
Authors: Strokov Vladimir , Fragione Giacomo , Berti Emanuele
Published: July 2023

Galactic nuclei are potential hosts for intermediate-mass black holes (IMBHs), whose gravitational field can affect the motion of stars and compact objects. The absence of observable perturbations in our own Galactic Centre has resulted in a few constraints on the mass and orbit of a putative IMBH. Here, we show that the Laser Interferometer Space Antenna (LISA) can further constrain these parameters if the IMBH forms a binary with a compact remnant (a white dwarf, a neutron star, or a stellar-mass black hole), as the gravitational-wave signal from the binary will exhibit Doppler-shift variations as it orbits around Sgr A*. We argue that this method is the most effective for IMBHs with masses $10^3\, \mathrm{ M}_\odot \lesssim M_{\rm IMBH}\lesssim 10^5\, \mathrm{ M}_\odot$ and distances of 0.1–2 mpc with respect to the supermassive black hole, a region of the parameter space partially unconstrained by other methods. We show that in this region the Doppler shift is most likely measurable whenever the binary is detected in the LISA band, and it can help constrain the mass and orbit of a putative IMBH in the centre of our Galaxy. We also discuss possible ways for an IMBH to form a binary in the Galactic Centre, showing that gravitational-wave captures of stellar-mass black holes and neutron stars are the most efficient channel.
Validation of semi-analytical, semi-empirical covariance matrices for two-point correlation function for early DESI data
Authors: Rashkovetskyi Michael , Eisenstein Daniel J , Aguilar Jessica Nicole , Brooks David , Claybaugh Todd , Cole Shaun , Dawson Kyle , de la Macorra Axel , Doel Peter , Fanning Kevin , Font-Ribera Andreu , Forero-Romero Jaime E , Gontcho A Gontcho Satya , Hahn ChangHoon , Honscheid Klaus , Kehoe Robert , Kisner Theodore , Landriau Martin , Levi Michael , Manera Marc , Miquel Ramon , Moon Jeongin , Nadathur Seshadri , Nie Jundan , Poppett Claire , Ross Ashley J , Rossi Graziano , Sanchez Eusebio , Saulder Christoph , Schubnell Michael , Seo Hee-Jong , Tarle Gregory , Valcin David , Weaver Benjamin Alan , Zhao Cheng , Zhou Zhimin , Zou Hu
Published: July 2023

We present an extended validation of semi-analytical, semi-empirical covariance matrices for the two-point correlation function (2PCF) on simulated catalogs representative of luminous red galaxies (LRGs) data collected during the initial 2 months of operations of the Stage-IV ground-based Dark Energy Spectroscopic Instrument (DESI). We run the pipeline on multiple effective Zel’dovich (EZ) mock galaxy catalogs with the corresponding cuts applied and compare the results with the mock sample covariance to assess the accuracy and its fluctuations. We propose an extension of the previously developed formalism for catalogs processed with standard reconstruction algorithms. We consider methods for comparing covariance matrices in detail, highlighting their interpretation and statistical properties caused by sample variance, in particular, non-trivial expectation values of certain metrics even when the external covariance estimate is perfect. With improved mocks and validation techniques, we confirm a good agreement between our predictions and sample covariance. This allows one to generate covariance matrices for comparable data sets without the need to create numerous mock galaxy catalogs with matching clustering, only requiring 2PCF measurements from the data itself. The code used in this paper is publicly available at https://github.com/oliverphilcox/RascalC.
Transmorph: a unifying computational framework for modular single-cell RNA-seq data integration
Authors: Fouché Aziz , Chadoutaud Loïc , Delattre Olivier , Zinovyev Andrei
Published: July 2023

Data integration of single-cell RNA-seq (scRNA-seq) data describes the task of embedding datasets gathered from different sources or experiments into a common representation so that cells with similar types or states are embedded close to one another independently from their dataset of origin. Data integration is a crucial step in most scRNA-seq data analysis pipelines involving multiple batches. It improves data visualization, batch effect reduction, clustering, label transfer, and cell type inference. Many data integration tools have been proposed during the last decade, but a surge in the number of these methods has made it difficult to pick one for a given use case. Furthermore, these tools are provided as rigid pieces of software, making it hard to adapt them to various specific scenarios. In order to address both of these issues at once, we introduce the transmorph framework. It allows the user to engineer powerful data integration pipelines and is supported by a rich software ecosystem. We demonstrate transmorph usefulness by solving a variety of practical challenges on scRNA-seq datasets including joint datasets embedding, gene space integration, and transfer of cycle phase annotations. transmorph is provided as an open source python package.
METABOLOGENOMIC CHARACTERIZATION UNCOVERS HETEROGENEITY AMONG IDH MUTANT GLIOMAS
Authors: Ajisebutu Andrew , Nassiri Farshad , Wang Justin Z , Mamatjan Yasin , Nejad Romina , Patil Vikas , Liu Jeff , Voisin Mathew R , Mansouri Sheila , Karimi Shirin , Chakravarthy Ankur , Chen Eric , De Carvalho Daniel D , Aldape Kenneth , Zadeh Gelareh
Published: July 2023

Mutations in isocitrate dehydrogenase (IDH) enzymes are recognised to drive the molecular footprint of diffuse gliomas, and patients with IDH-mutant gliomas have overall favorable outcomes compared to patients with IDH wildtype tumors. Nonetheless, survival can vary widely even amongst patients with IDH-mutant tumors. A comprehensive metabologenomic characterization of IDH-mutant gliomas has not been performed to date.

METHOD: Glioma samples from a cohort of 154 patients that underwent surgery at the UHN in Toronto, ON, underwent multiplatform molecular analysis, including metabolomic studies, genome- wide DNA methylation profiling and bulk RNA sequencing. A comprehensive, integrative analysis was performed, and validated through the use of an independent cohort derived from The Cancer Genome Atlas. RESULTS: We discovered a group of IDH-mutant gliomas with globally altered metabolism that highly resembled IDH wildtype tumors. Notably, these IDH-mutant gliomas with dysregulated metabolism were distinguished from their IDH-mutant counterparts by significantly shorter overall survival. The prognostic relevance of dysregulated metabolism complements, but was not wholly explained by canonically recognized prognostic classifications in IDH-mutant gliomas including 1p/19q codeletion, glioma CpG Island Hypermethylator (GCIMP) status and CDKN2A homozygous deletion. IDH-mutant tumors with dysregulated metabolism harbored distinct epigenetic alterations that converged to drive proliferative and stem-like transcriptional profiles. CONCLUSION: Utilizing a cross-platform analysis we have uncovered a novel subtyping of IDH-mutant gliomas with dysregulated cellular metabolism with similar survival to IDH-wildtype tumors. The metabolic profile provides unique information on glioma phenotypes, which may can facilitate a more comprehensive understanding of glioma biology, and provide a window to target novel dependencies.
SHH PATHWAY ACTIVATION DRIVES MALIGNANT TRANSFORMATION IN A SUBSET OF MPNSTS AND IS A POTENTIAL THERAPEUTIC TARGET
Authors: Suppiah Suganth , Mansouri Sheila , Liu Jeff , Patel Vikas , Bunda Severa , Zadeh Gelareh
Published: July 2023

BTFC travel award recipient

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann-cell derived sarcomas and the leading cause of mortality in Neurofibromatosis Type 1. The molecular pathways driving malignant transformation is not well understood. In this study, we leveraged multi-platform genomic and epigenomic profiling of human neurofibromas and MPNSTs to identify targetable molecular pathways that lead to malignant transformation. Fresh-frozen tumors (N = 108) were studied including methylation profiling, RNA sequencing, and whole exome sequencing. Unsupervised consensus clustering of methylome and transcriptome data identified 2 distinct MPNST subgroups. Pathway analysis showed that MPNST-G1 tumors are characterized by SHH pathway activation (NES=1.9952, p<0. 0001, FDR<0.001), while MPNST-G2 tumors are characterized by WNT pathway activation (NES=1.7630, p<0.0001, FDR=0.0058). We observed significantly higher rates of PTCH1 deletions, a negative regulator of SHH pathway, in MPNST-G1 (62.5% vs 0%, Fisher Exact Test=0.0065, p<0.05) and PTCH1 promoter hypermethylation (mean beta value: 0.2899 vs. 0.06119, p<0.05). A computational drug screen identified sonedigib, a SHH pathway inhibitor, as a potential treatment option for MPSNT-G1. We validated the importance of SHH pathway in malignant transformation by knocking out PTCH1 in neurofibroma cell lines and demonstrated increased cellular proliferation, cellular migration and invasion. In addition, treatment with sonedigib decreased cellular viability in MPNST cell lines and improved survival in mouse xenograft models. These results suggest a targeted approach should be taken for treating MPNSTs, and SHH and WNT pathway inhibition may be promising avenue for therapeutic development.