bluuebunny/crossref_metadata_2025_split huggingface dataset:
Breast Cancer Recurrence by Subtype in a Diverse, Contemporary Cohort of Young Women
Authors: Vuong Brooke , Darbinian Jeanne , Savitz Alison , Odele Patience , Perry Lauren M. , Sandhu Lakhbir , Habel Laurel , Kuehner Gillian 
Published: April 2023

Background:
Young breast cancer (YBC) patients are a unique subpopulation that are often underrepresented in randomized clinical trials. Furthermore, large national cancer databases lack detailed information on recurrence, a meaningful oncologic outcome for young patients.

Study Design:
Retrospective review of YBC patients (age ≤40) with Stage I-III breast cancer diagnosed from 2008 to 2018 was performed. Information on clinicopathologic characteristics, demographics, and outcomes were obtained from the electronic health record and chart review. Chi-square and Fisher exact tests were used for comparisons of categorical variables and parametric and nonparametric tests for continuous variables.

Results:
The cohort included 1,431 women with a median follow-up of 4.8 years (range: 0.3-12.9 years). The median age was 37 (IQR: 34-39). The study population included 598 (41.8%) White, 112 (7.8%) Black, 420 (29.4%) Asian/Pacific Islander, 281 (19.6%) Hispanic, and 20 (1.4%) “other” race/ethnicity patients. Tumor subtype was as follows: [1] Hormone Receptor (HR)+/HER2-, Grade (G) 1-2 =541 (37.8%); [2] HR+/HER2-, G3 =268 (18.7%); [3] HR+/HER2+ =262 (18.3%); [4] HR-/HER2+ =101 (7.1%); [5] HR-/HER2- =259 (18.1%). The majority (64.2%) presented with Stage II/III disease. There were 230 (16.1%) recurrences during follow-up; 74.8% were distant. Locoregional only recurrence was seen in 17/463 (3.7%) patients who underwent breast conservation versus 41/968 (4.2%) of patients undergoing mastectomy (p<0.001). Recurrence varied by tumor subtype: [1] HR+/HER2-, G1-2 (14.0%); [2] HR+/HER2-, G3 (20.9%); [3] HR+/HER2+ (11.1%); [4] HR-/HER2+ (22.8%); [5] HR-/HER2- (17.8%) (p=0.005).

Conclusion:
In this large, diverse YBC cohort, recurrences were most frequent among HR+/HER2-, G3 or HR-/HER2+ invasive tumors; most were distant. There were numerically similar locoregional-only recurrences after breast conservation versus mastectomy. Additional research is needed to identify predictors of recurrence.
Identification of a specific inflammatory protein biosignature in coronary and peripheral blood associated with increased risk of future cardiovascular events
Authors: Proudfoot Diane , Gigante Bruna , West Nick E.J. , Hoole Stephen P. , Strawbridge Rona J. , Tremoli Elena , Baldassarre Damiano , Williams Simon 
Published: April 2023

AbstractBackground and rationaleAs an adjunct to coronary intervention, the Liquid Biopsy System (LBS, PlaqueTec, UK) enables accurate intracoronary blood sampling at discrete sites simultaneously. We investigated variation between local coronary and remote (peripheral) blood levels of a panel of atherosclerosis-associated proteins and examined how this might relate to cardiovascular risk assessment.Methods and ResultsIn a previous proof-of-concept trial, coronary blood samples were collected using the LBS in 28 patients. For 12 of these patients, sampling was conducted across the uninstrumented lesion, prior to percutaneous coronary intervention (PCI). Peripheral blood samples were also collected, at baseline and after PCI. Protein levels in coronary and peripheral plasma samples were analysed by proximity extension assay (PEA, Olink).Before PCI, in 10 out of 12 patients, coronary levels of hepatocyte growth factor (HGF), pappalysin-1 (PAPPA) and spondin-1 (SPON1) were elevated compared with peripheral levels, in some cases >10-fold. Following PCI, involving iatrogenic plaque rupture prior to stenting, peripheral levels of these proteins were elevated to a similar degree as coronary levels. In 2 patients, peripheral elevations of HGF, PAPPA and SPON1 (all >90thcentile) were observed at baseline, prior to PCI. The protein pattern that was identified, consisting of high levels of a combination of HGF, PAPPA and SPON1 was absent in healthy control peripheral blood, but when investigated in baseline peripheral blood samples from reference cardiovascular and COVID-19 patient cohorts, was associated with the occurrence of major adverse cardiovascular events (MACE) and mortality.ConclusionsFrom investigation of coronary and peripheral blood samples, we identified a novel inflammatory protein signature, which when present in peripheral blood appears to portend worse outcomes. Measurement of these proteins could therefore aid identification of individuals at high risk of cardiovascular events or death.Translational PerspectiveThrough sampling of local coronary blood, we discovered a novel protein biosignature consisting of a combination of elevated levels of HGF, PAPPA and SPON1. When this biosignature was assessed in peripheral samples from reference cardiovascular and COVID-19 cohorts, it associated with the occurrence of MACE and mortality. The biosignature protein levels correlated with markers of mast cell and neutrophil activity but not with CRP, possibly indicating a specific inflammatory status. Early detection of this protein signal has potential clinical utility to identify specific patients at increased risk of poor outcomes.Graphical Abstract
Elevated blood pressure accelerates white matter brain aging among late middle-aged women: a Mendelian Randomization study in the UK Biobank
Authors: Feng Li , Ye Zhenyao , Mo Chen , Wang Jingtao , Liu Song , Gao Si , Ke Hongjie , Canida Travis A , Pan Yezhi , Hatch Kathryn S , Ma Yizhou , Chen Chixiang , Mitchell Braxton D. , Hong L.Elliot , Kochunov Peter , Chen Shuo , Ma Tianzhou 
Published: April 2023

AbstractBackgroundElevated blood pressure (BP) is a modifiable risk factor associated with cognitive impairment and cerebrovascular diseases. However, the causal effect of BP on white matter (WM) brain aging remains unclear.MethodsIn this study, we focused on N=219,968 non-pregnant, family-unrelated individuals of European ancestry who had genotype data and two non-null clinical BP measurements available (99,532 male and 120,436 female, mean age=56.55, including 16,901 participants with neuroimaging data available) collected from UK Biobank (UKB). We adopted a chronological age-adjusted brain age metric, Brain Age Gap (BAG), as the outcome variable to measure the brain aging status. As a first step, we established a machine learning model to compute BAG based on white matter microstructure integrity measured by fractional anisotropy (FA) derived from diffusion tensor imaging data in a training set of subjects without hypertension (N=7,728). We then performed a two-sample Mendelian Randomization (MR) analysis to estimate the causal effect of BP on WM BAG in the whole population and subgroups stratified by gender and age brackets using two non-overlapping data sets (N=20,3067 for the set with genotype and BP data but no FA data; and N=8,822 for the set with genotype, BP and FA data). The main MR method used was generalized inverse variance weighted (gen-IVW) with other MR methods also included as sensitivity analysis.ResultsThe hypertension group is on average 0.3098 years (95%CI=0.1313,0.4884; p <0.0001) older in WM brain age than the non-hypertension group of the same chronological age. Females are on average 0.8143 years (95% CI=0.6797 to 0.949; p <0.0001) younger in WM brain age than males of the same chronological age. The MR analyses showed an overall significant positive causal effect of diastolic blood pressure (DBP) on WM BAG, where every 10 mm Hg increase in DBP can lead to 0.371 years increase in brain age (CI: 0.034-0.709, p=0.0311). The stratified analysis by age and gender group found such significant causal effect of DBP on BAG to be most prominent among female women aged 50-59 (0.686 years/10mm Hg, CI: 0.054-1.318, p=0.0335) and aged 60-69 (0.962 years/10mm Hg, CI: 0.209-1.714, p=0.0122).ConclusionHypertension and genetic predisposition to higher BP can accelerate WM brain aging specifically targeting at late middle-aged women, providing insights on planning effective control of BP for women in this age group.
A high-throughput 3D kinetic killing assay
Authors: Zhao Renping , Yanamandra Archana K. , Qu Bin 
Published: April 2023

AbstractIn vivo, immune killer cells must infiltrate into tissues and search for their cognate target cells in 3D environments. To investigate the cytotoxic function of immune killer cells, there is currently a significant need for an in vitro kinetic assay that resembles 3D in vivo features. Our work presents a high-throughput kinetic killing assay in 3D that is a robust and powerful tool for evaluating the killing efficiency of immune killer cells, as well as the viability of tumor cells under in vivo-like conditions. This assay holds particular value for assessing primary human CTLs and NK cells and can also be applied to primary murine killer cells. By utilizing collagen concentrations to mimic healthy tissue, soft tumors, and stiff tumors, this assay enables the evaluation of cell function and behavior in physiologically and pathologically relevant scenarios, particularly in the context of solid tumors. Furthermore, this assay shows promise as a personalized strategy for selecting more effective drugs/treatments against tumors, using primary immune cells for individual patients to achieve improved clinical outcomes.
Genetic sex determination in three closely related hydrothermal vent gastropods, including one species with intersex individuals
Authors: Castel J , Pradillon F , Cueff V , Leger G , Daguin-Thiébaut C , Ruault S , Mary J , Hourdez S , Jollivet D , Broquet T 
Published: April 2023

AbstractMolluscs have a wide variety of sexual systems and have undergone many transitions from separate sexes to hermaphroditism or vice versa, which is of interest for studying the evolution of sex determination and differentiation. Following the serendipitous observation that sex was the primary driver of genetic structure in the hydrothermal vent gastropodAlviniconcha boucheti, we investigated sexual systems and sex determination in this species and two others of the same genus. We combined genome-wide multi-locus genotypes obtained from RAD sequencing with anatomical observations of the gonads of the threeAlviniconchaspecies occurring in the southwest Pacific Ocean:A. boucheti(n=199),A. strummeri(n=41 ind.) andA. kojimai(n=246). In two of the species (A. bouchetiandA. strummeri), the sexes are separate and genetically determined by a male-heterogametic (XY) system. External observation of the gonads in the third species (A. kojimai) also suggested that the sexes were separate, but histological analyses revealed that 76% of the individuals classified as females from external observation of the gonads presented a mosaic of male and female reproductive tissue. Empirical analyses and simulations showed nonetheless that 14 RAD loci were sex-linked with an XY signature inA. kojimai(as compared with 64 inA. strummeriand 373 inA. boucheti). Comparison across species and mapping of RAD loci to a non-contiguous reference genome assembly of the related speciesA. marisindicashowed that all sex-linked loci identified inA. kojimaiare located on five scaffolds that also contain 15 and 67 sex-linked RAD loci in the other two species, respectively. These results suggest that all threeAlviniconchaspecies share the same XY sex determination system, but that the gonad of XXA. kojimaiindividuals are invaded by a variable proportion of male reproductive tissue. It remains to be seen whether the male tissue in these intersex individuals is functional or not. The identification of Y-specific RAD loci (found only inA. boucheti) and the phylogenetic analysis of three sex-linked loci shared by all species suggested that X-Y recombination has evolved differently within each species. This situation of three species showing variation in gonadal development around a probably common sex determination system provides new insights into the reproductive mode of poorly known deep-sea species and questions the evolution of gametogenetic polymorphism in these species.
Structures of Langya virus fusion protein ectodomain in pre and post fusion conformation
Authors: May Aaron J. , Pothula Karunakar Reddy , Janowska Katarzyna , Acharya Priyamvada 
Published: April 2023

AbstractLangya virus (LayV) is a paramyxovirus in theHenipavirusgenus, closely related to the deadly Nipah and Hendra viruses, that was identified in August 2022 through disease surveillance following animal exposure in eastern China. Paramyxoviruses present two glycoproteins on their surface, known as attachment and fusion proteins, that mediate entry into cells and constitute the primary antigenic targets for immune response. Here, we determine cryo-EM structures of the uncleaved LayV fusion protein (F) ectodomain in pre- and post-fusion conformations. The LayV-F protein exhibits pre- and post-fusion architectures that, despite being highly conserved across paramyxoviruses, show differences in their surface properties, in particular at the apex of the prefusion trimer, that may contribute to antigenic variability. While dramatic conformational changes were visualized between the pre- and post-fusion forms of the LayV-F protein, several domains remained invariant, held together by highly conserved disulfides. The LayV-F fusion peptide is buried within a highly conserved, hydrophobic, interprotomer pocket in the pre-fusion state and is notably less flexible than the rest of the protein, highlighting its “spring-loaded” state and suggesting that the mechanism of pre-to-post transition must involve perturbations to the pocket and release of the fusion peptide. Together, these results offer a structural basis for how the Langya virus fusion protein compares to its Henipavirus relatives and propose a mechanism for the initial step of pre- to post-fusion conversion that may apply more broadly to paramyxoviruses.ImportanceThe Henipavirus genus is quickly expanding into new animal hosts and geographic locations. This study compares the structure and antigenicity of the Langya virus fusion protein to other henipaviruses, which has important vaccine or therapeutic development implications. Furthermore, the study proposes a new mechanism to explain the early steps of the fusion initiation process that can be more broadly applied to theParamyxoviridaefamily.
Organic matter influence on ooid formation: New insights into classic examples (Great Salt Lake, USA; Triassic Germanic Basin, Germany)
Authors: Pei Yu , Suarez-Gonzalez Pablo , Duda Jan-Peter , Reitner Joachim 
Published: April 2023

AbstractOoids are particles composed of a tangential or radial cortex growing around a nucleus. They are common in carbonate deposits of almost any geological age and provide insights into environmental conditions. However, abiotic or biotic factors influencing their formation remain unclear. This study aims to advance our understanding of ooid formation with a multi- analytical approach (e.g., FE-SEM, Raman spectroscopy, μ-XRF) to classic examples from Great Salt Lake (GSL; USA) and the Lower Triassic Germanic Basin (GB; Germany). Both deposits represent hypersaline shallow-water environments where ooids are closely associated with microbial mats. GSL ooids are dominantly 0.2–1 mm in size, ellipsoidal to subspherical in shape, composed of aragonite, and contain organic matter (OM). GB ooids are mainly ≤4 mm in size, spherical to subspherical in shape, composed of calcite, and currently contain little OM. Despite the differences, both ooids have the same cortex structures, likely reflecting similar formation processes. Some GSL ooids formed around detrital grains while others exhibit micritic particles in their nuclei. In GB ooids, detrital nuclei are rare, despite the abundance of siliciclastic particles of various sizes in the host rocks. GB deposits also include “compound ooids”, i.e., adjacent ooids that coalesced with each other during growth, suggesting staticin-situdevelopment, which is supported by the lack of detrital grains as nuclei. GB ooids also grew into laminated microbial crusts with identical microstructures, further indicating a static formation. Such microbial crusts typically form through mineral precipitation associated with OM (e.g., extracellular polymeric substances), suggesting a similar formation pathway for ooids. The inferred key-role of OM is further supported by features in radial ooids from the GSL, which commonly exhibit, from their nuclei towards their surface, increasing OM contents and decreasing calcification.
Kir7.1 is the physiological target for hormones and steroids that regulate uteroplacental function
Authors: Haoui Monika , Vergara Citlalli , Lishko Polina V. 
Published: April 2023

SummaryPreterm birth is a multifactorial syndrome that is detrimental to the well-being of both the mother and the newborn. During normal gestation, the myometrium is maintained in a quiescent state by the action of progesterone. As a steroid hormone, progesterone is thought to modify uterine and placental morphology by altering gene expression, but a nongenomic mode of action has long been suspected. Here we reveal that progesterone activates both human and murine inwardly rectifying potassium channel Kir7.1, which is expressed in mammalian myometrial smooth muscle and placental pericytes during late gestation. Kir7.1 is also activated by compounds used to prevent premature labor, including the progestogens 17-alpha-hydroxyprogesterone caproate and dydrogesterone, revealing an unexpected mode of action for these drugs. Our results reveal that Kir7.1 is the molecular target of a number of endogenous and synthetic steroids that control uterine excitability and placental function, and is therefore a promising therapeutic target to control utero-placental physiology and support healthy pregnancy.
Flexibility and sensitivity in gene regulation out of equilibrium
Authors: Mahdavi Sara , Salmon Gabriel L. , Daghlian Patill , Garcia Hernan G. , Phillips Rob 
Published: April 2023

Cells adapt to environments and tune gene expression by controlling the concentrations of proteins and their kinetics in regulatory networks. In both eukaryotes and prokaryotes, experiments and theory increasingly attest that these networks can and do consume bio-chemical energy. How does this dissipation enable cellular behaviors unobtainable in equilibrium? This open question demands quantitative models that transcend thermodynamic equilibrium. Here we study the control of a simple, ubiquitous gene regulatory motif to explore the consequences of departing equilibrium in kinetic cycles. Employing graph theory, we find that dissipation unlocks nonmonotonicity and enhanced sensitivity of gene expression with respect to a transcription factor’s concentration. These features allow a single transcription factor to act as both a repressor and activator at different levels or achieve outputs with multiple concentration regions of locally-enhanced sensitivity. We systematically dissect how energetically-driving individual transitions within regulatory networks, or pairs of transitions, generates more adjustable and sensitive phenotypic responses. Our findings quantify necessary conditions and detectable consequences of energy expenditure. These richer mathematical behaviors—feasibly accessed using biological energy budgets and rates—may empower cells to accomplish sophisticated regulation with simpler architectures than those required at equilibrium.Significance StatementGrowing theoretical and experimental evidence demonstrates that cells can (and do) spend biochemical energy while regulating their genes. Here we explore the impact of departing from equilibrium in simple regulatory cycles, and learn that beyond increasing sensitivity, dissipation can unlock more flexible input-output behaviors that are otherwise forbidden without spending energy. These more complex behaviors could enable cells to perform more sophisticated functions using simpler systems than those needed at equilibrium.
Modelling human KCNT1-epilepsy inDrosophila: a seizure phenotype and drug responses
Authors: Hussain Rashid , Lim Chiao Xin , Shaukat Zeeshan , Islam Anowarul , Caseley Emily A. , Lippiat Jonathan D. , Rychkov Grigori Y. , Ricos Michael G. , Dibbens Leanne M. 
Published: April 2023

AbstractMutations in theKCNT1potassium channel cause severe forms of epilepsy which are resistant to current treatments.In vitrostudies have shown thatKCNT1-epilepsy mutations are gain of function, significantly increasing K+current amplitudes. To investigate ifDrosophilacan be used to model humanKCNT1epilepsy, we generatedDrosophila melanogasterlines carrying humanKCNT1with the patient mutation G288S, R398Q or R928C. Expression of each mutant channel in GABAergic neurons gave a seizure phenotype which was sensitive to drugs currently used to treat patients withKCNT1-epilepsy. Cannabidiol showed the greatest reduction of the seizure phenotype while some drugs increased the seizure phenotype. Our study shows thatDrosophilacan be used to model humanKCNT1-epilepsy and potentially used as a tool to assess new treatments forKCNT1epilepsy.
Universal baleen whale microsatellite panel for individual identification and power to detect parentage
Authors: Suárez-Menéndez Marcos , Bérubé Martine , Bachmann Lutz , Best Peter , Heide-Jørgensen Mads Peter , Lesage Veronique , Oosting Tom , Prieto Rui , Ramp Christian , Robbins Jooke , Sears Richard , Silva Mónica A. , Tollis Marc , Vermeulen Els , Víkingsson Gísli A. , Wiig Øystein , Palsbøll Per J. 
Published: April 2023

AbstractHighly polymorphic single tandem repeat loci (STR, also known as microsatellite loci) remain a familiar, cost efficient class of markers for genetic analyses in ecology, behavior and conservation. We characterize a new universal set of ten STR loci (from 28 potential candidate loci) in seven baleen whale species, which are optimized for PCR amplification in two multiplex reactions along with a Y chromosome marker for sex determination. The optimized, universal set of STR loci provides an ideal starting point for new studies in baleen whales aimed at individual-based and population genetic studies, and facilitates data sharing among research groups. Data from the new STR loci were combined with genotypes from other published STR loci to assess the power to assign parentage (paternity) using exclusion in four species: fin whales, humpback whales, blue whales and bowhead whales. We argue that parentage studies should present a power analysis to demonstrate that the specific data are sufficiently informative to assign parentage with statistical rigor.