bluuebunny/crossref_metadata_2025_split huggingface dataset:
ZIP Code to Genomic Code
Authors: Goel Neha , Hernandez Alexandra E. , Antoni Michael H. , Kesmodel Susan , Pinheiro Paulo S. , Kobetz Erin , Merchant Nipun , Cole Steve 
Published: March 2024

Objective:
To determine the association between objective (geospatial) and subjective (perceived) measures of neighborhood disadvantage (ND) and aggressive breast cancer (BCa) tumor biology, defined using validated social adversity-associated transcription factor (TF) activity and clinical outcomes.

Summary Background Data:
ND is associated with shorter BCa recurrence-free survival (RFS), independent of individual, tumor, and treatment characteristics, suggesting potential unaccounted biological mechanisms by which ND influences RFS.

Methods:
We quantified TF-binding motif prevalence within promoters of differentially expressed genes for 147 tissue samples prospectively collected on protocol. Covariate-adjusted multivariable regression analyzed objective and subjective ND scores with 5 validated TFs of social adversity and aggressive biology—pro-inflammatory activity (NF-kB, AP-1), sympathetic nervous system (SNS) activity (CREB), and protective cellular responses (IRF, STAT). To clinically validate these TFs as prognostic biomarkers of aggressive biology, logistic regression and multivariable Cox proportional-hazards models analyzed their association with Oncotype DX scores and RFS, respectively.

Results:
Increasing objective ND was associated with aggressive tumor biology (up-regulated NF-kB, AP-1, down-regulated IRF, STAT) and SNS activation (up-regulated CREB). Increasing subjective ND (e.g., threat to safety), was associated with up-regulated NF-kB and CREB and down-regulated IRF. These TF patterns were associated with high-risk Oncotype DX scores and shorter RFS.

Conclusions:
In the largest human social genomics study, objective and subjective ND were significantly associated with TFs of aggressive biology and SNS activation. These TFs also correlated with worse clinical outcomes, implicating SNS activation as one potential mechanism behind ND survival disparities. These findings remain to be validated in a national cohort.
Obesity and Native Tissue Repairs: A Secondary Analysis of the OPTIMAL Trial
Authors: Hagedorn Meghan K. , Locklear Tonja M. , Evans Sarah , Karp Natalie E. , Greer W. Jerod 
Published: March 2024

Importance
The Operations and Pelvic Muscle Training in the Management of Apical Support Loss (OPTIMAL) Trial compared sacrospinous ligament fixation (SSLF) and uterosacral ligament suspension (ULS) surgical outcomes. Increasing body mass index (BMI) is associated with an increased risk of pelvic organ prolapse, and the prevalence of obesity is increasing worldwide.

Objective
The purpose of this study was to better understand the effect of obesity on the results of native tissue vaginal apical suspension procedures.

Study Design
This was a secondary analysis of the OPTIMAL Trial data set. Subgroup analysis was performed to compare surgical failure rates between SSLF and ULS across BMI subgroups after 2 years.

Results
There were 75, 120, 63, and 39 patients in the normal, overweight, class 1 obesity, and class 2 obesity or greater BMI subgroups, respectively. There were no statistically significant differences in surgical failure rates between SSLF and ULS within BMI subgroups; however, failure rates increased in the ULS group between the nonobese and obese groups (normal, 35.9% SSLF vs 30.6% ULS [P = 0.81]; overweight, 38.6% vs 30.2% [P = 0.44]; class 1 obesity, 38.7% vs 40.6% [P = 0.92]; class 2 obesity or greater, 21.1% vs 45% [P = 0.21]).

Conclusions
The risk of surgical failure between SSLF and ULS was not significant across BMI subgroups. Additional investigation is required to further elucidate whether SSLF or ULS is a more reliable option for obese patients.
Vaginal Estrogen Prescribing and Cost Trends Among Medicare Part D Beneficiaries
Authors: Tabakin Alexandra L. , Lee Wai , Winkler Harvey A. , Shalom Dara F. 
Published: March 2024

Importance
In 2016, the American College of Obstetricians and Gynecologists issued a Committee Opinion on the safety of vaginal estrogen (VE) in estrogen-dependent breast cancer patients. Since that time, prescribing trends of VE have not been studied.

Objective
Our objective was to analyze expenditure and prescribing trends of VE from 2016 to 2020 for Medicare Part D beneficiaries.

Study Design
In this retrospective review, we queried the Medicare Part D Spending and Prescriber Datasets from 2016 to 2020 to identify claims for VE. Trends regarding claims, expenditures, beneficiaries, and prescribers were examined. A subanalysis of the Medicare Part D Prescriber Dataset was performed for obstetrician-gynecologist-specific trends. Statistical analysis was done with the Kruskal-Wallis test.

Results
From 2016 to 2020 for all specialties, the number of VE claims decreased annually from 945,331 in 2016 to 320,571 in 2020. Most claims were for Estrace (49.5%) followed by Yuvafem (23.3%), Vagifem (14.5%), and Estring (12.7%). The number of VE prescribers decreased from 20,216 to 5,380, with obstetrician-gynecologists comprising 60% of all prescribers. Beneficiaries decreased by more than 70% from 439,210 to 123,318, whereas average spending per beneficiary increased from $688.52 to $1,027.55. Total annual spending on VE decreased from $277,891,645 to $106,679,580. However, average spending per claim increased from $293.40 to $355.28 and increased for all products besides Yuvafem.

Conclusions
Vaginal estrogen claims, beneficiaries, and total expenditures across all provider types have decreased from 2016 to 2020. However, spending per beneficiary and VE claims have increased. Our data suggest that utilization and accessibility of vaginal estrogen may be influenced, in part, by cost.
Aspartate aminotransferase and alanine aminotransferase elevation in suspected physical abuse: Can the threshold to obtain an abdominal computed tomography be raised?
Authors: Lee Ji Young , Coombs Carmen , Clarke Jennifer , Berger Rachel 
Published: March 2024

BACKGROUND
Identification of abdominal injury (AI) in children with concern for physical abuse is important, as it can provide important medical and forensic information. Current recommendations are to obtain screening liver function tests (LFTs) in all children with suspected physical abuse and an abdominal computed tomography (CT) when the aspartate aminotransferase (AST) or alanine aminotransferase (ALT) is >80 IU/L. This threshold to obtain an abdominal CT is lower than general trauma guidelines, which use a cutoff of AST >200 IU/L or ALT >125 IU/L.

METHODS
This was a retrospective review of children aged 0 to 60 months at a single pediatric tertiary care center who were evaluated for physical abuse and had AST or ALT >80 IU/L. Subjects were then stratified into two groups: midrange (AST ≤200 IU/L and ALT ≤125 IU/L) and high-range (AST >200 IU/L and/or ALT >125 IU/L) LFTs.

RESULTS
Abdominal CTs were performed in 55% (131 of 237) of subjects, 38% (50 of 131) with midrange LFTs and 62% (81 of 131) with high-range LFTs. Abdominal injury was identified in 19.8% (26 of 131) of subjects. Subjects with AI were older than those without AI (mean [SD] age, 18.7 [12.5] vs. 11.6 [12.2] months; p = 0.009). The highest yield of abdominal CTs positive for AI was in the group with high-range LFTs with signs or symptoms of AI at 52.0% (13 of 25; 95% confidence interval, 31.3–72.2%). The negative predictive value of having midrange LFTs and no signs or symptoms of AI was 100% (95% confidence interval, 97.0–100%).

CONCLUSION
Our data suggest that abdominal CT may not be necessary in children being evaluated for physical abuse who have AST ≤200 IU/L and ALT ≤125 IU/L and do not have signs or symptoms of AI. This could limit the number of abdominal CTs performed.

LEVEL OF EVIDENCE
Diagnostic Test/Criteria; Level IV.
Shifting our attention earlier in the multiple sclerosis disease course
Authors: Epstein Samantha E. , Longbrake Erin E. 
Published: March 2024

Purpose of review
Revisions of multiple sclerosis (MS) diagnostic criteria enable clinicians to diagnose patients earlier in the biologic disease course. Prompt initiation of therapy correlates with improved clinical outcomes. This has led to increased attention on the earliest stages of MS, including the MS prodrome and radiologically isolated syndrome (RIS). Here, we review current understanding and approach to patients with preclinical MS.

Recent findings
MS disease biology often begins well before the onset of typical MS symptoms, and we are increasingly able to recognize preclinical and prodromal stages of MS. RIS represents the best characterized aspect of preclinical MS, and its diagnostic criteria were recently revised to better capture patients at highest risk of conversion to clinical MS. The first two randomized control trials evaluating disease modifying therapy use in RIS also found that treatment could delay or prevent onset of cli
nical disease.

Summary
Despite progress in our understanding of the earliest stages of the MS disease course, additional research is needed to systematically identify patients with preclinical MS as well as capture those at risk for developing clinical disease. Recent data suggests that preventive immunomodulatory therapies may be beneficial for high-risk patients with RIS; though management remains controversial.
Evolutionary trajectory of TRPM2 channel activation by adenosine diphosphate
ribose and calcium
Authors: Ma Cheng , Luo Yanping , Zhang Congyi , Cheng Cheng , Hua Ning , Liu Xiaocao , Wu Jianan , Qin Luying , Yu Peilin , Luo Jianhong , Yang Fan , Jiang Lin-Hua , Zhang Guojie , Yang Wei 
Published: March 2024

Abstract
Ion channel activation upon ligand gating triggers a myriad of biological
events and, therefore, evolution of ligand gating mechanism is of fundamental
importance. TRPM2, a typical ancient ion channel, is activated by adenosine
diphosphate ribose (ADPR) and calcium and its activation has evolved from a
simple mode in invertebrates to a more complex one in vertebrates, but the
evolutionary process is still unknown. Molecular evolutionary analysis of TRPM2s
from more than 280 different animal species has revealed that, the C-terminal
NUDT9-H domain has evolved from an enzyme to a ligand binding site for
activation, while the N-terminal MHR domain maintains a conserved ligand binding
site. Calcium gating pattern has also evolved, from one
Ca2+-binding site as in sea anemones to three sites as
in human. Importantly, we identified a new group represented by olTRPM2, which
has a novel gating mode and fills the missing link of the channel gating
evolution. We conclude that the TRPM2 ligand binding or activation mode evolved
through at least three identifiable stages in the past billion years from simple
to complicated and coordinated. Such findings benefit the evolutionary
investigations of other channels and proteins.
Unbiased complexome profiling and global proteomics analysis reveals mitochondrial impairment and potential changes at the intercalated disk in presymptomatic R14Δ/+mice hearts
Authors: Foo Brian , Amedei Hugo , Kaur Surmeet , Jaawan Samir , Boshnakovska Angela , Gall Tanja , de Boer Rudolf A. , Silljé Herman H.W. , Urlaub Henning , Rehling Peter , Lenz Christof , Lehnart Stephan E. 
Published: March 2024

AbstractBackgroundPhospholamban (PLN) is a sarco-endoplasmic reticulum (SER) membrane protein that regulates cardiac contraction/relaxation by reversibly inhibiting the SERCA2a Ca2+-reuptake pump. The R14Δ-PLN mutation causes severe cardiomyopathy that is resistant to conventional treatment. Protein complexes and higher-order supercomplexes such as intercalated disk components and Ca+2-cycling domains underlie many critical cardiac functions, a subset of which may be disrupted by R14Δ-PLN.MethodsWe developed an improved complexome profiling (CP) workflow specifically geared towards identifying disruption of very high molecular-weight (>2 MDa) protein complexes and supercomplexes in presymptomatic R14Δ/+mice hearts. Ventricular tissues were homogenized under non-denaturing conditions, fractionated by size-exclusion chromatography (SEC) and subjected to quantitative data-independent acquisition mass spectrometry (DIA-MS) proteomics analysis. Systematic analysis of CP data using conventional strategies yielded limited insights, likely due to underrepresentation of cardiac-specific complexes in the curated protein complex databases used as ground-truth for analysis. We thus developed PERCOM: a novel data analysis strategy that does not rely upon protein complex databases and can, furthermore, be implemented on widely available spreadsheet software.ResultsSEC-DIA-MS coupled with PERCOM identified 296 proteins with disrupted elution profiles in presymptomatic 28wk-old R14Δ/+mice. Hits were significantly enriched for mitochondrial and intercalated disk (ICD) components. Alterations to mitochondrial and ICD supercomplexes were observed in mice as young as 9wks of age and were associated with reduced expression of mitochondrial proteins and maximal oxygen consumption rate.ConclusionUsing a novel CP workflow, we identify mitochondrial alterations as an early-stage R14Δ-PLN event and provide preliminary data showing effects at the ICD. These molecular components underlie critical cardiac functions and their alteration at a young age may contribute to R14Δ-PLN pathogenesis.
Reassembly of a tropical rainforest ecosystem: A new chronosequence in the Ecuadorian Chocó tested with the recovery of tree attributes
Authors: Escobar Sebastián , Newell Felicity L. , Endara María-José , Guevara-Andino Juan E. , Landim Anna R. , Neuschulz Eike Lena , Nußer Ronja , Müller Jörg , Pedersen Karen M. , Schleuning Matthias , Tremlett Constance J. , Villa-Galaviz Edith , Schaefer H. Martin , Donoso David A , Blüthgen Nico 
Published: March 2024

AbstractFrom hunting and foraging to clearing land for agriculture, humans modify forest biodiversity, landscapes, and climate. Forests constantly undergo disturbance–recovery dynamics and understanding them is a major objective of ecologists and conservationists. Chronosequences are a useful tool for understanding global restoration efforts. They represent a space-for-time substitution approach suited for the quantification of theresistanceof ecosystem properties to withstand disturbance and theresilienceof these properties until reaching pre-disturbance levels. Here we introduce a newly established chronosequence with 62 plots (50 ⍰ 50 m) in active cacao plantations and pastures, early and late regeneration, and mature old-growth forests, across a 200 km2 area in the extremely wet Chocó rainforest. Our chronosequence covers by far the largest total area of plots compared to others in the Neotropics. Plots ranged from 159–615 masl in a forested landscape with 74 ± 2.8 % forest cover within a 1-km radius including substantial old-growth forest cover. Land-use legacy and regeneration time were not confounded by elevation. We tested how six forest structure variables (maximum tree height and DBH, basal area, number of stems, vertical vegetation heterogeneity, and light availability), aboveground biomass (AGB), and rarefied tree species richness change along our chronosequence. Forest structure variables, AGB, and tree species richness increased with regeneration time and are predicted to reach similar levels to those in old-growth forests after ca. 30–116, 202, and 108 yrs, respectively. Compared to previous work in the Neotropics, old-growth forests in Canandé accumulate high AGB that takes one of the largest time spans reported until total recovery. Our chronosequence comprises one of the largest tree species pools, covers the largest total area of regenerating and old-growth forests, and has higher forest cover than other Neotropical chronosequences. Hence, our chronosequence can be used to determine the time for recovery and stability (resistance and resilience) of different taxa and ecosystem functions, including species interaction networks. This integrative effort will ultimately help to understand how one of the most diverse forests on the planet recovers from large-scale disturbances.
DNA damage drives antigen diversification through mosaic Variant Surface Glycoprotein (VSG) formation inTrypanosoma brucei
Authors: Smith Jaclyn E. , Wang Kevin J. , Kennedy Erin M. , Hakim Jill M.C. , So Jaime , Beaver Alexander K. , Magesh Aishwarya , Gilligan-Steinberg Shane D. , Zheng Jessica , Zhang Bailin , Moorthy Dharani Narayan , Akin Elgin Henry , Mwakibete Lusajo , Mugnier Monica R. 
Published: March 2024

SummaryAntigenic variation, using large genomic repertoires of antigen-encoding genes, allows pathogens to evade host antibody. Many pathogens, including the African trypanosomeTrypanosoma brucei,extend their antigenic repertoire through genomic diversification. While evidence suggests thatT. bruceidepends on the generation of new variant surface glycoprotein (VSG) genes to maintain a chronic infection, a lack of experimentally tractable tools for studying this process has obscured its underlying mechanisms. Here, we present a highly sensitive targeted sequencing approach for measuring VSG diversification. Using this method, we demonstrate that a Cas9-induced DNA double-strand break within the VSG coding sequence can induce VSG recombination with patterns identical to those observed during infection. These newly generated VSGs are antigenically distinct from parental clones and thus capable of facilitating immune evasion. Together, these results provide insight into the mechanisms of VSG diversification and an experimental framework for studying the evolution of antigen repertoires in pathogenic microbes.
Attentional modulation of secondary somatosensory and visual thalamus of mice
Authors: Petty Gordon H , Bruno Randy M 
Published: March 2024

ABSTRACTEach sensory modality has its own primary and secondary thalamic nuclei. While the primary thalamic nuclei are well understood to relay sensory information from the periphery to the cortex, the role of secondary sensory nuclei is elusive. We trained head-fixed mice to ateend to one sensory modality while ignoring a second modality, namely to ateend to touch and ignore vision, or vice versa. Arrays were used to record simultaneously from secondary somatosensory thalamus (POm) and secondary visual thalamus (LP). In mice trained to respond to tactile stimuli and ignore visual stimuli, POm was robustly activated by touch and largely unresponsive to visual stimuli. A different pateern was observed when mice were trained to respond to visual stimuli and ignore touch, with POm now more robustly activated during visual trials. This POm activity was not explained by differences in movements (i.e., whisking, licking, pupil dilation) resulting from the two tasks. Post hoc histological reconstruction of array tracks through POm revealed that subregions varied in their degree of plasticity. LP exhibited similar phenomena. We conclude that behavioral training reshapes activity in secondary thalamic nuclei. Secondary nuclei respond to the same behaviorally relevant, reward-predicting stimuli regardless of stimulus modality.
How do we respond to the next SARS CoV epidemic/pandemic? A bioinformatics approach with the promise of preventing or reducing the severity of future SARS CoV related pandemics
Authors: Geoffrey A S Ben , Gracia Judith 
Published: March 2024

AbstractIn this work, we develop a Bayesian weighted scheme to generate evolutionary lineages of a particular viral protein sequence of interest and through a process of clustering and choosing representative lineages from the different clusters according to an evolutionary fitness objective function, we demonstrate it is possible to have anticipated the emergence of the SARS-CoV 2 (2019) strain from the SARS-CoV 1(2004) strain and having shown this retrospectively, we discuss the possibility of applying this approach along with continuous genomic surveillance of SARS-CoVs to prevent or reduce severity of future SARS-CoV related pandemics by being prepared with broad neutralization strategies for anticipated future lineages of SARS-CoVs identified through bioinformatics approaches such as that reported in this work.
Unexpectedly low recombination rates and presence of hotspots in termite genomes
Authors: Everitt Turid , Rönneburg Tilman , Elsner Daniel , Olsson Anna , Liu Yuanzhen , Larva Tuuli , Korb Judith , Webster Matthew T 
Published: March 2024

AbstractMeiotic recombination is a fundamental evolutionary process that facilitates adaptation and the removal of deleterious genetic variation. Social Hymenoptera exhibit some of the highest recombination rates among metazoans, whereas high recombination rates have not been found among non-social species from this insect order. It is unknown whether elevated recombination rates are a ubiquitous feature of all social insects. In many metazoan taxa, recombination is mainly restricted to hotspots a few kilobases in length. However, little is known about the prevalence of recombination hotspots in insect genomes. Here we infer recombination rate and its fine-scale variation across the genomes of two social species from the insect order Blattodea: the termitesMacrotermes bellicosusandCryptotermes secundus. We used linkage-disequilibrium-based methods to infer recombination rate. We infer that recombination rates are close to 1 cM/Mb in both species, similar to the average metazoan rate. We also observed a highly punctate distribution of recombination in both termite genomes, indicative of the presence of recombination hotspots. We infer the presence of full-lengthPRDM9genes in the genomes of both species, which suggests recombination hotspots in termites might be determined byPRDM9, as they are in mammals. We also find that recombination rates in genes are correlated with inferred levels of germline DNA methylation. The finding of low recombination rates in termites indicates that eusociality is not universally connected to elevated recombination rate. We speculate that the elevated recombination rates in social Hymenoptera are instead promoted by intense selection among haploid males.