bluuebunny/crossref_metadata_2025 huggingface dataset:
Four changing look active galactic nuclei found from optical variations
Authors: Zhu Li-Tao , Li Jie , Wang Zhongxiang , Zhang Ju-Jia
Published: April 2024

We report the finding of four changing look (CL) Active Galactic Nuclei (AGN). We selected these sources due to their potential as interesting targets when considering their relatively large optical flux variations and related mid-infrared flux variations. To identify their CL feature, we use archival spectra from the Sloan Digital Sky Survey (SDSS) taken at least 8 yr ago as well as spectra taken recently from the Transient Name Server (TNS) and with the 2.4-m LiJiang telescope (LJT). We study the sources’ spectral changes by fitting and determining the Hα and Hβ components and verify their CL behaviour. When comparing the TNS and/or LJT spectra to the SDSS ones, all four sources showed the appearance of a broad or a stronger broad Hα component and a relatively weak broad Hβ component. As two of the four sources are established to have a brighter-and-bluer feature in the photometric data, during the time periods in which the TNS and LJT spectra were taken, this feature likely accompanied the turn-on of the broad components. Thus, we suggest that this brighter-and-bluer feature can be used as a criterion for efficiently finding CL sources among previously spectroscopically classified type 2 AGN, such as from among the sources provided by the SDSS.
Deep-PK: deep learning for small molecule pharmacokinetic and toxicity prediction
Authors: Myung Yoochan , de Sá Alex G C , Ascher David B
Published: April 2024

Evaluating pharmacokinetic properties of small molecules is considered a key feature in most drug development and high-throughput screening processes. Generally, pharmacokinetics, which represent the fate of drugs in the human body, are described from four perspectives: absorption, distribution, metabolism and excretion—all of which are closely related to a fifth perspective, toxicity (ADMET). Since obtaining ADMET data from in vitro, in vivo or pre-clinical stages is time consuming and expensive, many efforts have been made to predict ADMET properties via computational approaches. However, the majority of available methods are limited in their ability to provide pharmacokinetics and toxicity for diverse targets, ensure good overall accuracy, and offer ease of use, interpretability and extensibility for further optimizations. Here, we introduce Deep-PK, a deep learning-based pharmacokinetic and toxicity prediction, analysis and optimization platform. We applied graph neural networks and graph-based signatures as a graph-level feature to yield the best predictive performance across 73 endpoints, including 64 ADMET and 9 general properties. With these powerful models, Deep-PK supports molecular optimization and interpretation, aiding users in optimizing and understanding pharmacokinetics and toxicity for given input molecules. The Deep-PK is freely available at https://biosig.lab.uq.edu.au/deeppk/.
Proximal telomeric decompaction due to telomere shortening drives FOXC1-dependent myocardial senescence
Authors: Li Bin , Xiong Weiyao , Zuo Wu , Shi Yuanyuan , Wang Teng , Chang Lingling , Wu Yueheng , Ma Heng , Bian Qian , Chang Alex C Y
Published: April 2024

Telomeres, TTAGGGn DNA repeat sequences located at the ends of eukaryotic chromosomes, play a pivotal role in aging and are targets of DNA damage response. Although we and others have demonstrated presence of short telomeres in genetic cardiomyopathic and heart failure cardiomyocytes, little is known about the role of telomere lengths in cardiomyocyte. Here, we demonstrate that in heart failure patient cardiomyocytes, telomeres are shortened compared to healthy controls. We generated isogenic human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) with short telomeres (sTL-CMs) and normal telomeres (nTL-CMs) as model. Compared to nTL-CMs, short telomeres result in cardiac dysfunction and expression of senescent markers. Using Hi-C and RNASeq, we observe that short telomeres induced TAD insulation decrease near telomeric ends and this correlated with a transcription upregulation in sTL-CMs. FOXC1, a key transcription factor involved in early cardiogenesis, was upregulated in sTL-CMs and its protein levels were negatively correlated with telomere lengths in heart failure patients. Overexpression of FOXC1 induced hiPSC-CM aging, mitochondrial and contractile dysfunction; knockdown of FOXC1 rescued these phenotypes. Overall, the work presented demonstrate that increased chromatin accessibility due to telomere shortening resulted in the induction of FOXC1-dependent expression network responsible for contractile dysfunction and myocardial senescence.
DetSpace: a web server for engineering detectable pathways for bio-based chemical production
Authors: Martín Lázaro Hèctor , Marín Bautista Ricardo , Carbonell Pablo
Published: April 2024

Tackling climate change challenges requires replacing current chemical industrial processes through the rational and sustainable use of biodiversity resources. To that end, production routes to key bio-based chemicals for the bioeconomy have been identified. However, their production still remains inefficient in terms of titers, rates, and yields; because of the hurdles found when scaling up. In order to make production more efficient, strategies like automated screening and dynamic pathway regulation through biosensors have been applied as part of strain optimization. However, to date, no systematic way exists to design a genetic circuit that is responsive to concentrations of a given target compound. Here, the DetSpace web server provides a set of integrated tools that allows a user to select and design a biological circuit that performs the sensing of a molecule of interest by its enzymatic conversion to a detectable molecule through a transcription factor. In that way, the DetSpace web server allows synthetic biologists to easily design biosensing routes for the dynamic regulation of metabolic pathways in applications ranging from genetic circuits design, screening, production, and bioremediation of bio-based chemicals, to diagnostics and drug delivery.
Plato's Symposium
Authors: Nails Debra
Published: April 2024

David Halperin (Halperin 1992), cited under Platonic Methods of Composition, does not exaggerate when he says that Plato’s Symposium “remains beyond dispute the finest work of fiction, of prose literature, to survive from the classical period—as well as one of the trickiest texts of all time to interpret” (p. 127). It is debated across disciplinary boundaries including literary theory, political studies, theology, education, feminism, history, rhetoric, psychoanalysis, and queer studies. Interpretation might be less tricky if the Symposium were not also philosophy of the highest caliber, intensely controversial on a wide array of issues. Ostensibly about ΕΡΩΣ which, as “Eros” or “Love,” is the name of a divinity, but as “erōs” or “love” is the passionate desire for sex with someone, the dialogue embraces human aspiration, attraction, beauty, the good, human mortality, virtue, and happiness. In no other dialogue is there so resonant an account of Platonic forms, or of how desire (erōs) to understand the forms operates to achieve its end. In no other dialogue is the route to virtuous human happiness (eudaimonia) so explicitly detailed as here, governed by the desire to have permanent possession of what is good. The arguments of the Symposium sit uncomfortably with the Phaedo on immortality, the Phaedrus on paiderasteia, and the Theaetetus on midwifery. For many readers, however, such tricky philosophical issues are not so enduring an allure as Plato’s dramatic direction and exquisite characterizations—especially of Socrates. The setting is young Agathon’s drinking party in celebration of the prize he has just won for his first tragedies. His guest list includes, besides his lover Pausanias, the orator Phaedrus, the physician Eryximachus, Socrates, and the great comic playwright Aristophanes. The guests take turns giving speeches of praise (encomia) to ΕΡΩΣ, then the drunken Alcibiades crashes the party and praises Socrates instead. Plato’s Symposium—because of its marvelous variety—has lent itself to thousands of published works, of which only a tiny selection can be recommended here, but this selection will lead to the others through their discussions and notes.
International Human Trafficking
Authors: Enrile Annalisa
Published: April 2024

A solid introduction to the overall topic of international human trafficking is given in the United Nations Convention against Transnational Organized Crime (UNTOC) of 2000, known as the Palermo Protocol, which defines human trafficking as “the recruitment, transportation, transfer, harboring or receipt of persons by means of threat or use of force or other forms of coercion, of abduction, of fraud, of deception, of the abuse of power or of a position of vulnerability or of the giving or receiving of payments or benefits to achieve the consent of a person having control over another person, for the purpose of exploitation.” The Palermo Protocol set forth the first internationally agreed-upon language regarding human trafficking, with 179 countries (as of 2021) signing on to support it. The protocol focuses on Four Ps: prevention, protection, prosecution, and partnership. The broadest understandings of this definition are practiced to address situations that may cause human trafficking, such as poverty, creating a “coercion” based on economic detriment. Countries have developed their own variations on this definition and policies since then but have adhered to the spirit and overall definition laid out by the protocol. The United States Department of State annually releases the Trafficking in Persons Report (TIP Report), which is the most comprehensive resource for governmental anti-trafficking efforts and prevalence of the problem. The reporting countries are then ranked in tiers according to how effective their anti-trafficking efforts are. It is important to note, however, that though it is comprehensive, the TIP Report has received criticism for its level of credibility (as it relies on self-disclosure, there may be inflation of efforts reported) and that tier rankings are used to grant funding for programs (accordingly, those countries who may need funding may not receive it). Human trafficking and modern-day slavery is an epidemic that occurs domestically and internationally. According to the 2021 Global Estimates of Modern Slavery (composed by the International Labour Organization [ILO], Walk Free, and the International Organization for Migration [IOM]), at any given time, there are 50 million people around the world who are trafficked or living in conditions of slavery. Of this number, 27.6 million are victims of forced labor around the world. This reflects the most recent count and agreement of human trafficking and modern slavery statistics of forced labor, sex trafficking, and forced marriage. Of those who are trafficked, 55 percent are women and girls—mostly exploited in sex trafficking. It is estimated that the profit from human trafficking is approximately 150 billion dollars.
Canada in World War II
Authors: Sarty Roger
Published: April 2024

Canada’s substantial and wide-ranging part in the Allied military and economic effort in the Second World War led Canadian leaders to coin the term “middle power,” that is, ranking behind only the great powers. From a population of about 11 million, the country put 1.1 million in uniform, half of whom served in air, land, and naval forces overseas primarily in the Atlantic and European theaters. They fought largely under British higher command, Canada having come to nationhood as part of the British Empire/Commonwealth with armed forces modeled on the British forces. The economic effort was larger still. Canadian-made military equipment (some three times as much as needed by Canadian forces), food, lumber, and industrial resources supplied Allied nations around the world. The war was transformative for the country. Burgeoning US power and Britain’s parlous position brought a decisive shift in the balance in Canada’s international relations to its neighbor to the south. One result of the change from the familiar corridors of power in London to Washington, where Canada had much less influence, was the dramatic growth of the small Canadian foreign service more effectively to press the country’s interests. Major Canada-US initiatives included a permanent alliance for the defense of North America that is still fundamental to continental security, and the integration of defense production in the two countries. Canada as much as the United States became an “arsenal of democracy,” producing artillery, small arms, explosives, electronics including radar and naval sonar, military vehicles (more than 800,000), aircraft, warships, and merchant ships, with an industrial work force of nearly one million men and women. These undertakings, together with the supply of food and raw materials to allied nations, had an enormous economic and social impact. The grim austerity of the Great Depression gave way to a boom, laying foundations for the country’s modern industrial economy, and providing the government revenues needed to launch the early programs of the modern welfare state, including generous benefits to war veterans. An existential issue for Canadian war policy was historic tensions between the English-speaking majority of the population, which tended to favor support for Britain, and the large Francophone minority centered in the province of Quebec, which did not. Those divisions had been severely aggravated by the imposition of conscription to reinforce the army corps Canada raised for the British Expeditionary Force during the First World War. In the Second World War the government exercised extreme caution in the mobilization of manpower, restricting military conscription to home service until the final months of the war when heavy battlefield losses necessitated the dispatch of a limited number of the conscripts overseas. The war effort did stimulate French-Canadian nationalisme, but not large-scale civil unrest.
Legal Circumventions in Rabbinic Law
Authors: Stein Hain Elana
Published: April 2024

Rabbinic law is known for fine distinctions, what some call “hair-splitting” logic. While such logic leads to nuanced discussions about how to fulfill the Divine will, it also makes legal circumventions available. From the Latin circumvenīre, meaning to “come around,” circumventions are used to get around the implications of law. Ancient rabbinic literature, composed from the third to the seventh century ce in Roman Palestine and Sassanian Babylonia, contains many legal circumventions. Some are explicit rabbinic decrees, while others are implicit, such as exegesis that narrows or expands biblical injunctions. There is also a rabbinic term for legal circumvention: ha’aramah (literally, “subtlety” or “cunning”). Examples of ha’aramah sometimes resemble legal loopholing by changing aspects of a scenario to alter what law applies there (e.g., where a sale is forbidden, it is replaced by a gift and counter-gift); other examples involve structuring the proper intentions to render a certain activity permissible where it would otherwise be forbidden (e.g., moving livestock on a Festival day with the intention of preparing it as food is permitted, while moving livestock on a Festival day merely because it is in the wrong place is forbidden). Legal loopholing is often connected to legal fictions or presumptions: where people/courts rely on presumptions that are partially or fully known to be false. Indeed, fictions and loopholes have some jurisprudential thinking in common, but they are not interchangeable mechanisms. In Jewish law, some legal fictions are meant to circumvent law (e.g., where a lost husband who returns after his wife has remarried is told that the court does not believe his identity), while other fictions have nothing to do with circumventing law, but only creative abstract constructions of reality (e.g., viewing the wall of a sukkah as extending upward when there is a gap between the walls and the roof of the sukkah). Insofar as religious law may be presumed to require a sincere desire to perform the divine lawgiver’s commandments, loopholes and fictions seem out of place in religious law. This entry includes writings that offer legal, historical, and social logic for rabbinic circumventions generally, and also for particular circumventions. It also includes works that examine the broader jurisprudential issues that circumvention logic entails, including nominalism and the role of intention in Jewish law. While this entry reflects the logic of legal circumventions introduced in late antique rabbinic literature, it also includes material about the legal loopholes and fictions that developed after the close of the Talmud and are widely known and used in society today.
Geography and Sustainability Education at the School Level
Authors: Windsor Sally , Lee Shu Jun , Kriewaldt Jeana
Published: April 2024

Scholars are in broad agreement that studying geography is a core component of mainstream schooling which can contribute to sustainability education. Numerous emphases that transcend geography have developed extolling the importance of holistic education, scientific knowledge, interconnected thinking, and the utopian desire to transform society and schools. School transformation is a lofty goal that requires schools to rethink what they teach, how they teach in the lessons explicitly taught in their curriculum, their co-curricular undertakings, and the implicit activities that together are the fabric of what is taught and what may be learned. Current global conceptions of sustainability education, i.e., education for sustainable development (ESD), arose from critiques that traditional environmental education based only in the natural sciences could not satisfactorily address the interlinked human and societal issues that pre-empt or cause ecological destruction and environmental issues, and the imperative, now, that is climate change. Based on the United Nations’ well-established Sustainable Development Goals (SDGs), ESD aims to give all people the knowledge, skills, values, and agency to address global challenges. Geography uniquely promotes human-environment thinking, which is essential for considering sustainable futures. Geography education is inherently concerned about the future and thus plays a vital role in helping young people imagine sustainable futures and bring about transformative change. Geography, with its embedded use of spatial technologies and measurements within observations, enables and makes visible the explicit linking of human and natural systems. Other aspects of sustainability education in geography have received less attention. Critical geography is, at best, only gently making its way into schools. There is consideration of social justice in geography education, yet few accounts from the perspective of those who are oppressed exist. The belief that the solution can be achieved by incremental individual actions when education fails to ask students to critically assess the impacts of consumerism and capitalism on those who live in poverty is being challenged.
Gut dysbiosis impairs intestinal renewal and lipid absorption in Scarb2 deficiency-associated neurodegeneration
Authors: Li Yinghui , Liu Xingchen , Sun Xue , Li Hui , Wang Shige , Tian Wotu , Xiang Chen , Zhang Xuyuan , Zheng Jiajia , Wang Haifang , Zhang Liguo , Cao Li , Wong Catherine C L , Liu Zhihua
Published: April 2024

Scavenger receptor class B, member 2 (SCARB2) is linked to Gaucher disease and Parkinson’s disease. Deficiency in the SCARB2 gene causes progressive myoclonus epilepsy (PME), a rare group of inherited neurodegenerative diseases characterized by myoclonus. We found that Scarb2 deficiency in mice leads to age-dependent dietary lipid malabsorption, accompanied with vitamin E deficiency. Our investigation revealed that Scarb2 deficiency is associated with gut dysbiosis and an altered bile acid pool, leading to hyperactivation of FXR in intestine. Hyperactivation of FXR impairs epithelium renewal and lipid absorption. Patients with SCARB2 mutations have a severe reduction in their vitamin E levels and cannot absorb dietary vitamin E. Finally, inhibiting FXR or supplementing vitamin E ameliorates the neuromotor impairment and neuropathy in Scarb2 knockout mice. These data indicate that gastrointestinal dysfunction is associated with SCARB2 deficiency-related neurodegeneration, and SCARB2-associated neurodegeneration can be improved by addressing the nutrition deficits and gastrointestinal issues.
Precarious Transitions: How Precarious Employment Shapes Parental Coresidence among Young Adults
Authors: Lei Lei , Mai Quan D
Published: April 2024

The rise of precarious work generates important questions about how this mode of employment might affect young workers’ transition to adulthood, particularly their decision to live independently. Existing demographic literature has considered the impact of unemployment on parental coresidence but overlooked the potential influence of precarious employment. Yet, features of precarious employment might matter for young adults’ residential arrangements. Our paper provides a theoretical framework linking precarious work to parental coresidence. Specifically, we outline three mechanisms that underlie this relationship: low pay, meager benefits, and short job tenure. Using longitudinal data from the National Longitudinal Survey of Youth from 2005 to 2017, we provide empirical support for our model. We found that precariously employed young adults are more likely than their peers in standard jobs to live with their parents. About a third of this effect can be accounted for by the three theorized mechanisms. Our research contributes to the growing literature demonstrating the impact of economic insecurity on the workplace and family, the two essential arenas of social life.
“The Ties that Bind are those that Punish: Network Polarization and Federal Crime Policy Gridlock, 1979–2005”
Authors: Duxbury Scott W
Published: April 2024

Largely overlooked in research on criminal legal expansion is the rise of political polarization and its attendant consequences for crime policy. Drawing on theories of intergroup collaboration and policymaking research, I argue that network polarization—low frequencies of collaborative relations between lawmakers belonging to distinct political groups—negatively affects crime legislation passage by reducing information flows, increasing intergroup hostility, and creating opportunities for political attacks. To evaluate this perspective, I recreate dynamic legislative networks between 1979 and 2005 using data on 1,897,019 cosponsorship relationships between 1537 federal lawmakers and the outcomes of 5950 federal crime bills. Results illustrate that increases in partisan network segregation and the number of densely clustered subgroups both have negative effects on bill passage. These relationships are not moderated by majority party status and peak during the 1990s and early 2000s, a period when prison growth showed its first signs of slowing. These findings provide new insight to the relationship between polarization and policy and suggest that increases in network polarization may be partly responsible for declines in crime policy adoption observed in recent decades.
Study on factors contributing to severity of ship collision accidents in the Yangtze River estuary
Authors: Gao Xinjia , Dai Wei , Yu Lu , Yu Qifeng
Published: April 2024

The Yangtze River estuary in China is characterized by a complex maritime geographical environment and presents significant challenges to ship manoeuvring and control, thereby increasing the risk of ship collision accidents. Based on the 2013–2022 shipwreck investigation report published by Shanghai and Zhejiang Maritime Safety Administration, this paper analyses the primary factors responsible for ship collision accident severity in the Yangtze River estuary from four aspects, namely ship, environment, human and management. Utilizing accident severity as the dependent variable and 24 factors, including ship type, gross tonnage, wind speed, operational errors and so on, as independent variables, the study employed a stepwise regression approach to filter the variables. Subsequently, an ordered probit regression model was constructed based on the 10 most influential variables, followed by a marginal effect analysis. The findings indicate that a ship's gross tonnage, wind speed, ocean current speed, offshore distance and day/night conditions significantly influence the likelihood of different accident levels. Specifically, wind speed, offshore distance and ocean current speed have a negative impact on minor and general accidents while positively affecting major and severe accidents. Gross tonnage and daytime/nighttime have a positive impact on minor and general accidents but negatively impact major and severe accidents. Moreover, general accidents exhibit the most pronounced marginal effect for each explanatory variable. The findings can help the shipping authorities to identify the causes of ship collision accidents and take effective measures to reduce such accidents, thereby enhancing the safety of ship navigation in the area.
The relationship of vitamin D to the MHAQ index, activity disease, and inflammation in a sample of Syrian rheumatoid disease patients
Authors: Shahada Zienab , Kudsi Maysoun , Youssef Lama , Kabalan Younes
Published: April 2024

Background:

Vitamin D has an immunomodulatory and anti-inflammatory role, and its deficiency has been linked with many autoimmune disorders, including rheumatoid arthritis (RA). The correlation ship between the severity of RA and serum levels of vitamin D is a subject of immense interest and therapeutic implications.

Patients and Methods:

A total of 100 patients previously diagnosed with RA were collected from visitors to the rheumatology clinic at the university hospital and their ages were over 18 years. The serum vitamin D value and the C-reactive protein (CRP) value were measured, and the Disease Activity Score CRP28 (DAS28CRP) and Modified Health Assessment Questionnaire (MHAQ) score were calculated to determine the severity and effectiveness of the disease and its relationship to vitamin D deficiency.

Results:

The average age of the patients ranged according to the patient’s age (46.03±11.291), we note that individuals whose ages ranged from 26 to 65 accounted for the largest percentage (94%), 83% of women (83) and 17% men (17), and the mean score for sun exposure was 15.80±5.446. Patients were individuals diagnosed with the disease between 5 and 10 years were the highest group, with a percentage of 31%. A total of 72% of the patients were not treated with corticosteroids, and 43% of the patients were treated with vitamin D. We found that the number of patients using biologic medications was 18%, and the number of patients using disease-modifying anti-rheumatic drugs was 88%. The mean of DAS28 was moderate in 63% of patients, and the average of the MHAQ score was 0.80±0.334. We found that there is no statically significant correlation between the serum vitamin D level and DAS28/CRP (P=0.733), and there is also no statically significant correlation between the serum value of vitamin D and the medications used, whether biological or disease-modifying anti-rheumatic drugs (P=0.361). In addition, there is also no significant correlation between the serum vitamin D level and MHAQ score (P=0.100).

Conclusion:

There was no significant relationship between vitamin D deficiency and the disease activity or severity in a sample of patients with RA.
Race-Conscious Research Using Extracorporeal Life Support Organization Registry Data: A Narrative Review
Authors: Moynihan Katie M. , Sharma Meesha , Mehta Anuj , Lillie Jon , Ziegenfuss Marc , Festa Marino , Chan Titus , Thiagarajan Ravi
Published: April 2024

Race-conscious research identifies health disparities with 1) rigorous and responsible data collection, 2) intentionality and considered analyses, and 3) interpretation of results that advance health equity. Individual registries must overcome specific challenges to promote race-conscious research, and this paper describes ways to achieve this with a focus on the international Extracorporeal Life Support Organization (ELSO) registry. This article reviews ELSO registry publications that studied race with outcomes to consider whether research outputs align with race-conscious concepts and describe the direction of associations reported. Studies were identified via secondary analysis of a comprehensive scoping review on ECMO disparities. Of 32 multicenter publications, two (6%) studied race as the primary objective. Statistical analyses, confounder adjustment, and inclusive, antibiased language were inconsistently used. Only two (6%) papers explicitly discussed mechanistic drivers of inequity such as structural racism, and five (16%) discussed race variable limitations or acknowledged unmeasured confounders. Extracorporeal Life Support Organization registry publications demonstrated more adverse ECMO outcomes for underrepresented/minoritized populations than non-ELSO studies. With the objective to promote race-conscious ELSO registry research outputs, we provide a comprehensive understanding of race variable limitations, suggest reasoned retrospective analytic approaches, offer ways to interpret results that advance health equity, and recommend practice modifications for data collection.
Adjusting Atrial Size Parameters for Body Surface Area
Authors: Kirkbride Rachael R. , Aviram Galit , Heidinger Benedikt H. , Liberman Yuval , Libauske Aurelija , Liubauskas Rokas , Tridente Daniela M. , Brook Alexander , DaBreo Dominique C. , Monteiro Filho Antonio C. , Carroll Brett J. , Matos Jason D. , McCormick Ian C. , Manning Warren J. , Litmanovich Diana E.
Published: April 2024

Purpose:

Small left atrial (LA) volume was recently reported to be one of the best predictors of acute pulmonary embolism (PE)-related adverse events (AE). There is currently no data available regarding the impact that body surface area (BSA)-indexing of atrial measurements has on the association with PE-related adverse events. Our aim is to assess the impact of indexing atrial measurements to BSA on the association between computed tomography (CT) atrial measurements and AE.

Materials and Methods:

Retrospective study (IRB: 2015P000425). A database of hospitalized patients with acute PE diagnosed on CT pulmonary angiography (CTPA) between May 2007 and December 2014 was reviewed. Right and left atrial volume, largest axial area, and axial diameters were measured. Patients undergo both echocardiographies (from which the BSA was extracted) and CTPAs within 48 hours of the procedure. The patient’s body weight was measured during each admission. LA measurements were correlated to AE (defined as the need for advanced therapy or PE-related mortality at 30 days) before and after indexing for BSA. The area under the ROC curve was calculated to determine the predictive value of the atrial measurements in predicting AE.

Results:

The study included 490 acute PE patients; 62 (12.7%) had AE. There was a significant association of reduced BSA-indexed and non-indexed LA volume (both <0.001), area (<0.001 and 0.001, respectively), and short-axis diameters (both <0.001), and their respective RA/LA ratios (all <0.001) with AE. The AUC values were similar for BSA-indexed and non-indexed LA volume, diameters, and area with LA volume measurements being the best predictor of adverse outcomes (BSA-indexed AUC=0.68 and non-indexed AUC=0.66), followed by non-indexed LA short-axis diameter (indexed AUC=0.65, non-indexed AUC=0.64), and LA area (indexed AUC=0.64, non-indexed AUC=0.63).

Conclusion:

Adjusting for BSA does not substantially affect the predictive ability of atrial measurements on 30-day PE-related adverse events, and therefore, this adjustment is not necessary in clinical practice. While LA volume is the better predictor of AE, LA short-axis diameter has a similar predictive value and is more practical to perform clinically.
Improved Python Package for DNA Sequence Encoding using Frequency Chaos Game Representation
Authors: Halder Abhishek , Piyush  , Mathew Bernadette , Sengupta Debarka
Published: April 2024

Frequency Chaos Game Representation (FCGR), an extended version of Chaos Game Representation (CGR), emerges as a robust strategy for DNA sequence encoding. The core principle of the CGR algorithm involves mapping a onedimensional sequence representation into a higher-dimensional space, typically in the two-dimensional spatial domain. This paper introduces a use case wherein FCGR serves as a kmer frequency-based encoding method for motif classification using a publicly available dataset.

Availability and implementation

The FCGR python package, use case, along with additional functionalities, is available in theGitHub. Our FCGR package demonstrates superior accuracy and computational efficiency compared to a leading R-based FCGR library [1], which is designed for versatile tasks, including proteins, letters, and amino acids with user-defined resolution. Nevertheless, it is important to note that our Python package is specifically designed for DNA sequence encoding, where the resolution is predetermined based on the kmer length. It is a drawback of our current package compared to the state-of-the-art R-based kaos package [1].
Planar Optical Tweezer Trap (2D-LOT) System Realized by Light Sheet Illumination & Orthogonal Widefield Detection
Authors: Baro Neptune , Mondal Partha Pratim
Published: April 2024

We report the realization of the first planar optical tweezer trap system by a sheet of light. To visualize the trapping of the target object (dielectric bead or live cell) in a plane, an orthogonal widefield detection is employed. The planar / two-dimensional lightsheet optical tweezer (2D-LOT) sub-system is realized in an inverted microscopy mode with illumination from the bottom. A 1064 nm laser (power ∼ 500mW) is expanded and directed to a combination of cylindrical lens and high NA objective lens to generate a tightly-focused diffraction-limited light sheet. The object to be trapped is injected in the specimen chamber (consists of two coverslips placed at a distance of ≈ 1mm) using a syringe. The solution containing the objects stayed in the chamber due to the surface tension of the fluid. The illumination of trap-laser light is along Z-direction (with coverslip along XZ-plane) whereas, the detection is achieved perpendicular to the coverslip (along Y-axis). The orthogonal detection is employed to directly visualize the trapping in a plane. To better visualize the specimen, a separate white light illumination sub-system is used. The characterization of system PSF estimates the size of light sheet trap PSF to be, 2073.84µm2which defines the active trap region / area. Beads are tracked on their way to the trap region for determining the trap stiffness along Z and X i.e,kz= 1.13 ± 0.034pN/µmandkx= 0.74±0.021pN/µm. Results (image and video) show real-time trapping of dielectric beads in the trap zone (2D plane) generated by the light sheet. The beads can be seen getting trapped from all directions in the XZ-plane. Prolonged exposure to the light sheet builds up a 2D array of beads in the trap zone. Similar experiments on live NIH3T3 cells show cells trapped in the 2D trap. The potential of the planar trap lies in its ability to confine objects in two dimensions, thereby opening new kinds of experiments in biophysics, atomic physics, and optical physics.

Statement of Significance

The ability to trap and confine objects in two dimensions / a plane is an incredible feat that paves the way for new experiments in physical and biological sciences. Currently, no technique can achieve two-dimensional trapping of objects. Such a trap is realized by a sheet of light generating a near-rectangular potential trap-zone, enabling tweezing confined to a plane. This is unlike existing point-focus-based tweezers that are capable of point-potential well. The technique is expected to have widespread applications in science and engineering.
Integrating Transmission Dynamics and Pathogen Evolution Through a Bayesian Approach
Authors: Stolz Ugnė , Stadler Tanja , Vaughan Timothy G.
Published: April 2024

The collection of pathogen samples and subsequent genetic sequencing enables the reconstruction of phylogenies, shedding light on transmission dynamics. However, many existing phylogenetic methods fall short by neglecting within-host diversity and the impact of transmission bottlenecks, leading to inaccuracies in understanding epidemic spread. This paper introduces theTransmission Tree (TnT)model, which leverages multiple pathogen gene trees to more accurately model transmission history. By extending the Bayesian phylogenetic analysis softwareBEAST2, TnTintegrates the sampled ancestor birth-death model for transmission trees and the multi- species coalescent model for pathogen gene trees. This integration allows for the consideration of critical factors like transmission orientation, incomplete lineage sorting, and within- and between-host diversity. Notably,TnTincorporates an analytical approach to address unobserved transmission events, crucial in scenarios with incomplete sampling. Through theoretical evaluation and application to real-world cases like HIV transmission chains, we demonstrate thatTnToffers a robust solution to improve understanding of epidemic dynamics by effectively combining pathogen gene sequences and clinical data.
Arabidopsis WALL-ASSOCIATED KINASES are not required for oligogalacturonide-induced signaling and immunity
Authors: Herold Laura , Hua Chenlei , Kohorn Bruce , Nürnberger Thorsten , DeFalco Thomas , Zipfel Cyril
Published: April 2024

Carbohydrate-based cell wall signaling impacts plant growth, development, and stress responses; however, how cell wall signals are perceived and transduced remains poorly understood. Several cell wall breakdown products have been described as typical damage-associated molecular patterns (DAMPs) that activate plant immunity, including pectin-derived oligogalacturonides (OGs). Receptor kinases (RKs) of the WALL-ASSOCIATED KINASE (WAK) family have been shown to bind pectin and OGs, and were previously proposed as OG receptors. However, unambiguous genetic evidence for the role of WAKs in OG responses is lacking. Here, we investigated the role of Arabidopsis WAKs in OG perception using a novel deletion mutant of the clusteredWAKfamily. Using a combination of immune assays for early and late pattern-triggered immunity (PTI), we show that WAKs are dispensable for OG-induced signaling and immunity, indicating that they are notbona fideOG receptors.
Sex-based difference in immune responses and efficacy of the pneumococcal conjugate vaccine
Authors: Tchalla Essi Y. I. , Betadpur Anagha , Khalil Andrew Y. , Bhalla Manmeet , Bou Ghanem Elsa N.
Published: April 2024

Vaccine-mediated protection and susceptibility toStreptococcus pneumoniae(pneumococcus) infections are influenced by biological sex. The incidence of invasive pneumococcal disease remains higher in males compared to females even after the introduction of the pneumococcal conjugate vaccine (PCV). However, sex-based differences in the immune response to this conjugate vaccine remain unexplored. To investigate those differences, we vaccinated adult male and female mice with PCV and assessed cellular and humoral immune responses. Compared to females, male mice displayed lower levels of T follicular helper cells, germinal center B cells and plasmablasts, which are all required for antibody production following vaccination. This was linked to lower IgG and IgM levels against pneumococci and lower isotype switching to IgG3 in vaccinated males. Additionally, sera of vaccinated male mice had lower efficacy in several anti-pneumococcal functions including neutralization of bacterial binding to pulmonary epithelial cells as well as direct cytotoxicity againstS. pneumoniae. Importantly, while the vaccine was highly protective in females, vaccinated males succumbed to infection more readily and were more susceptible to both lung-localized infection and systemic spread followingS. pneumoniaechallenge. These findings identify sex-based differences in immune responses to PCV that can inform future vaccine strategies.
Muscle-fiber specific genetic manipulation of Drosophila sallimus severely impacts neuromuscular development, morphology, and physiology
Authors: Michael Andrew H. , Hana Tadros A. , Mousa Veronika G. , Ormerod Kiel G.
Published: April 2024

The ability of skeletal muscles to contract is derived from the unique genes and proteins expressed within muscles, most notably myofilaments and elastic proteins. Here we investigated the role of the sallimus (sls) gene, which encodes a structural homologue of titin, in regulating development, structure, and function ofDrosophila melanogaster. Ubiquitous knockdown ofslsusing RNA interference (RNAi) in all muscle fibers resulted in embryonic lethality. A screen for muscle-specific drivers revealed a Gal4 line that expresses in a single larval body wall muscle in each abdominal hemisegment. Disruptingslsexpression in single muscle fibers did not impact egg or larval viability nor gross larval morphology, but did significantly alter the morphology of individual muscle fibers. Analysis of individual sarcomeres revealed significant changes in ultrastructural organization, dramatically increasing sarcomere, I-band, A-band, andsls-band lengths. Surprisingly, muscle-cell specific disruption ofslsalso severely impacted neuromuscular junction (NMJ) formation. The extent of motor-neuron (MN) innervation along disrupted muscles was significantly reduced along with the number of glutamatergic boutons, in MN-Is and MN-Ib. Electrophysiological recordings revealed a 40% reduction in excitatory junctional potentials correlating with the extent of motor neuron loss. Analysis of active zone (AZ) composition revealed changes in presynaptic scaffolding protein (brp) abundance, but no changes in postsynaptic glutamate receptors. Ultrastructural changes in muscle and NMJ development at these single muscle fibers were sufficient to lead to observable changes in neuromuscular transduction and ultimately, locomotory behavior.
GALEON: A Comprehensive Bioinformatic Tool to Analyse and Visualise Gene Clusters in Complete Genomes
Authors: Pisarenco Vadim A. , Vizueta Joel , Rozas Julio
Published: April 2024

Motivation

Gene clusters, defined as a set of genes encoding functionally-related proteins, are abundant in eukaryotic genomes. Despite the increasing availability of chromosome-level genomes, the comprehensive analysis of gene family evolution remains largely unexplored, particularly for large and highly dynamic gene families or those including very recent family members. These challenges stem from limitations in genome assembly contiguity, particularly in repetitive regions such as large gene clusters. Recent advancements in sequencing technology, such as long reads and chromatin contact mapping, hold promise in addressing these challenges.

Results

To facilitate the identification, analysis, and visualisation of physically clustered gene family members within chromosome-level genomes, we introduce GALEON, a user-friendly bioinformatic tool. GALEON identifies gene clusters by studying the spatial distribution of pairwise physical distances among gene family members along with the genome-wide gene density. The pipeline also enables the simultaneous analysis and comparison of two gene families, and allows the exploration of the relationship between physical and evolutionary distances. This tool offers a novel approach for studying the origin and evolution of gene families.

Availability and Implementation

GALEON is freely available fromhttp://www.ub.edu/softevol/galeon, and fromhttps://github.com/molevol-ub/galeon
A new robust and accurate two-sample Mendelian randomization method with a large number of genetic variants
Authors: Zhang Lei , Niu Jun-Jie , He Xian-Mei , Zheng Xiao , Zhao Qi-Gang , Yu Xiu-Juan , Luo Li , Ren Hai-Gang , Pei Yu-Fang
Published: April 2024

Horizontal pleiotropy can significantly confound causal estimates in Mendelian randomization (MR) studies, particularly when numerous instrumental variables (IVs) are employed. In this study we propose a novel statistical method, Mendelian Randomization analysis based on Z-scores (MRZ), to conduct robust and accurate MR analysis in the presence of pleiotropy. MRZ models the IV-outcome association z-score as a mixture distribution, separating the causal effect of the exposure on the outcome from pleiotropic effects specific to each IV. By classifying IVs into distinct categories (valid, uncorrelated pleiotropic, and correlated pleiotropic), MRZ constructs a likelihood function to estimate both causal and pleiotropic effects. Simulation studies demonstrate MRZ's robustness, power, and accuracy in identifying causal effects under diverse pleiotropic scenarios and overlapped samples. In a bidirectional MR analysis of appendicular lean mass (ALM) and four lipid traits using both the UK Biobank (UKB)-internal datasets and the UKB-Global Lipids Genetics Consortium (GLGC) joint datasets, MRZ consistently identified a causal effect of ALM on total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). Conversely, existing methods often detected mutual causal relationship between lipid traits and ALM, highlighting their susceptibility to confounding by horizontal pleiotropy. A randomized controlled experiment conducted in mice validated the absence of causal effect of TC on ALM, corroborating the MRZ findings and further emphasizing its resilience against pleiotropic biases.
Orange Maker: a CRISPR/Cas9-mediated genome editing and screening project to generate orange-eyed DarkJedi GAL4 lines by undergraduate students
Authors: Park Hee Su , Gross Anna C. , Oh Seungjae , Kim Nam Chul
Published: April 2024

One of the greatest strengths ofDrosophilagenetics is its easily observable and selectable phenotypic markers. The mini-white marker has been widely used as a transgenic marker for Drosophila transgenesis. Flies carrying a mini-white construct can exhibit various eye colors ranging from pale orange to intense red, depending on the insertion site and gene dosage. Because the two copies of the mini-white marker show a stronger orange color, this is often used for selecting progenies carrying two transgenes together in a single chromosome after chromosomal recombination. However, some GAL4 lines available in the fly community originally have very strong red eyes. Without employing another marker, such as GFP, generating a recombinant chromosome with the strong red-eyed GAL4 and a desired UAS-transgene construct may be difficult. Therefore, we decided to change the red eyes of GAL4 lines to orange color. To change the eye color of the fly, we tested the CRISPR/Cas9 method with a guide RNA targeting the white gene with OK371-GAL4 and elav-GAL4. After a simple screening, we have successfully obtained multiple lines of orange-eyed OK371-GAL4 and elav-GAL4 that still maintain their original expression patterns. All of these simple experiments were performed by undergraduate students, allowing them to learn about a variety of different genetic experiments and genome editing while contributing to the fly research community by creating fruit fly lines that will be used in real-world research.