bluuebunny/crossref_metadata_2025_split huggingface dataset:
From isolated polyelectrolytes to star-like assemblies: the role of sequence heterogeneity on the statistical structure of the intrinsically disordered neurofilament-low tail domain
Authors: Kravikass Mathar , Koren Gil , Saleh Omar A. , Beck Roy 
Published: February 2024

Abstract
Intrinsically disordered proteins (IDPs) are a subset of proteins that lack stable secondary structure. Given their polymeric nature, previous mean-field approximations have been used to describe the statistical structure of IDPs. However, the amino-acid sequence heterogeneity and complex intermolecular interaction network have significantly impeded the ability to get proper approximations. One such case is the intrinsically disordered tail domain of neurofilament low (NFLt), which comprises a 50 residue-long uncharged domain followed by a 96 residue-long negatively charged domain. Here, we measure two NFLt variants to identify the impact of the NFLt two main subdomains on its complex interactions and statistical structure. Using synchrotron small-angle x-ray scattering, we find that the uncharged domain of the NFLt induces attractive interactions that cause it to self-assemble into star-like polymer brushes. On the other hand, when the uncharged domain is truncated, the remaining charged N-terminal domains remain isolated in solution with typical polyelectrolyte characteristics. We further discuss how competing long- and short-ranged interactions within the polymer brushes dominate their ensemble structure and, in turn, their implications on previously observed phenomena in NFL native and diseased states.

Graphic abstract
Visual schematic of the SAXS measurement results of the Neurofilament-low tail domain IDP (NFLt). NFLts assemble into star-like brushes through their hydrophobic N-terminal domains (marked in blue). In increasing salinity, brush height (h) is initially increased following a decrease while gaining additional tails to their assembly. Isolating the charged sub-domain of the NFLt (marked in red) results in isolated polyelectrolytes
Contraction Decomposition in Unit Disk Graphs and Algorithmic Applications in Parameterized Complexity
Authors: Panolan Fahad , Saurabh Saket , Zehavi Meirav 
Published: February 2024

We give a new decomposition theorem in unit disk graphs (UDGs) and demonstrate its applicability in the fields of Structural Graph Theory and Parameterized Complexity. First, our new decomposition theorem shows that the class of UDGs admits an “almost” Contraction Decomposition Theorem. Prior studies on this topic exhibited that the classes of planar graphs [Klein, SICOMP, 2008], graphs of bounded genus [Demaine, Hajiaghayi and Mohar, Combinatorica 2010], and
H
-minor free graphs [Demaine, Hajiaghayi and Kawarabayashi, STOC 2011] admit a Contraction Decomposition Theorem. Even
bounded-degree
UDGs can contain arbitrarily large cliques as minors, and therefore our result is a significant advance in the study of contraction decompositions. Additionally, this result answers an open question posed by Hajiaghayi (
www.youtube.com/watch?v=2Bq2gy1N01w
) regarding the existence of contraction decompositions for classes of graphs beyond
H
-minor free graphs though under a relaxation of the original formulation.

Second, we present a “parameteric version” of our new decomposition theorem. We prove that there is an algorithm that, given a UDG
G
and a positive integer
k
, runs in polynomial time and outputs a collection of

\(\mathcal {O}(k)\)

tree decompositions of
G
with the following properties. Each bag in any of these tree decompositions can be partitioned into

\(\mathcal {O}(k)\)

connected pieces (we call this measure the chunkiness of the tree decomposition). Moreover, for any subset
S
of at most
k
edges in
G
, there is a tree decomposition in the collection such that
S
is
well preserved
in the decomposition in the following sense. For any bag in the tree decomposition and any edge in
S
with both endpoints in the bag, either its endpoints lie in different pieces or they lie in a piece that is a clique. Having this decomposition at hand, we show that the design of parameterized algorithms for some cut problems becomes elementary. In particular, our algorithmic applications include single-exponential (or slightly super-exponential) algorithms for well-studied problems such as
Min Bisection
,
Steiner Cut
,

s
-Way Cut

, and
Edge Multiway Cut-Uncut
on UDGs; these algorithms are substantially faster than the best-known algorithms for these problems on general graphs.
ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts
Authors: Hu Bomiao , Wiesehöfer Marc , de Miguel Fernando J. , Liu Zongzhi , Chan Lok-Hei , Choi Jungmin , Melnick Mary Ann , Arnal Estape Anna , Walther Zenta , Zhao Dejian , Lopez-Giraldez Francesc , Wurtz Anna , Cai Guoping , Fan Rong , Gettinger Scott , Xiao Andrew , Yan Qin , Homer Robert , Nguyen Don X. , Politi Katerina 
Published: February 2024

Abstract

The majority of EGFR mutant lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors (TKI). However, most of these responses are partial, with drug-tolerant residual disease remaining even at the time of maximal response. This residual disease can ultimately lead to relapses, which eventually develop in most patients. To investigate the cellular and molecular properties of residual tumor cells in vivo, we leveraged patient-derived xenograft (PDX) models of EGFR mutant lung cancer. Subcutaneous EGFR mutant PDXs were treated with the third-generation TKI osimertinib until maximal tumor regression. Residual tissue inevitably harbored tumor cells that were transcriptionally distinct from bulk pretreatment tumor. Single-cell transcriptional profiling provided evidence of cells matching the profiles of drug-tolerant cells present in the pretreatment tumor. In one of the PDXs analyzed, osimertinib treatment caused dramatic transcriptomic changes that featured upregulation of the neuroendocrine lineage transcription factor ASCL1. Mechanistically, ASCL1 conferred drug tolerance by initiating an epithelial-to-mesenchymal gene-expression program in permissive cellular contexts. This study reveals fundamental insights into the biology of drug tolerance, the plasticity of cells through TKI treatment, and why specific phenotypes are observed only in certain tumors.

Significance:
Analysis of residual disease following tyrosine kinase inhibitor treatment identified heterogeneous and context-specific mechanisms of drug tolerance in lung cancer that could lead to the development of strategies to forestall drug resistance.
See related commentary by Rumde and Burns, p. 1188
Macrophages Under the Influence of Tumor Mesothelin Weaken Host Defenses against Pancreatic Cancer Metastasis
Authors: Alewine Christine 
Published: February 2024

Abstract
Although pancreatic cancer is a systemic disease that metastasizes early in its course, the signaling systems that promote this behavior remain incompletely understood. In this issue of Cancer Research, Luckett and colleagues identify a paracrine signaling pathway between cancer cells and macrophages that promotes pancreatic cancer metastasis. The authors used immunocompetent murine pancreatic cancer models with high versus low metastatic potential, genetic knockout and complementation strategies, and The Cancer Genome Atlas human data to demonstrate that tumor-secreted mesothelin repolarizes tumor and lung macrophages to a tumor-supportive phenotype. The repolarized macrophages increase secretion of VEGF and S100A9, raising local concentrations. In turn, VEGF enhances colony formation of cancer cells, while S100A9 promotes the recruitment of neutrophils to the lungs and the formation of neutrophil extracellular traps that support tumor metastasis. Together, these findings reveal a systemic signaling pathway that promotes pancreatic cancer metastasis by co-opting macrophages typically protective against cancer to instead promote its spread.
See related article by Luckett et al., p. 527
Prognostic Value of Pretreatment Plasma C-Reactive Protein in Patients with Early-Stage Breast Cancer
Authors: Andersen Høgni H. , Bojesen Stig E. , Johansen Julia S. , Ejlertsen Bent , Berg Tobias , Tuxen Malgorzata , Madsen Kasper , Danø Hella , Flyger Henrik , Jensen Maj-Britt , Nielsen Dorte L. 
Published: February 2024

Abstract

Background:
Breast cancer incidence is now the highest among all cancers and accountable for 6.6% of all cancer-related deaths worldwide. Studies of the prognostic utility of plasma C-reactive protein (CRP) measurement in early-stage breast cancer have given discrepant results.

Methods:
We identified 6,942 patients in the Danish Breast Cancer Cooperative Group database with early-stage breast cancer diagnosed between 2002 and 2016 who had a measure of pretreatment plasma CRP. Outcomes were recurrence-free interval and survival for a period up to 10 years. We analyzed associations with plasma CRP using Fine-Gray proportional subdistribution hazards model with recurrence-free interval. Data on plasma CRP were analyzed per doubling of concentration and in relation to CRP levels of &lt;3 mg/L, 3 to 10 mg/L, and &gt;10 mg/L and stratified according to standard clinical parameters in sensitivity analyses.

Results:
A doubling of the plasma CRP concentration was associated with increased risk of recurrence (multivariate adjusted HR, 1.05; 95% CI, 1.01–1.08) and shorter survival (HR, 1.13; 95% CI, 1.09–1.16) in multivariate analyses. Survival was shorter in patients with plasma CRP levels of 3 to 10 and &gt;10 mg/L versus &lt;3 mg/L, with multivariate adjusted HRs of 1.30; 95% CI, 1.17–1.45 and 1.65; 95% CI, 1.39–1.95, respectively.

Conclusions:
Elevated plasma CRP measured before treatment in patients with early-stage breast cancer is an independent biomarker of increased risk of recurrence and early death.

Impact:
CRP measures before treatment might be used to individualize follow-up of patients with early-stage breast cancer.
Co-clinical Trial of Novel Bispecific Anti-HER2 Antibody Zanidatamab in Patient-Derived Xenografts
Authors: DiPeri Timothy P. , Evans Kurt W. , Wang Bailiang , Zhao Ming , Akcakanat Argun , Raso Maria Gabriela , Rizvi Yasmeen Q. , Zheng Xiaofeng , Korkut Anil , Varadarajan Kaushik , Uzunparmak Burak , Dumbrava Ecaterina E. , Pant Shubham , Ajani Jaffer A. , Pohlmann Paula R. , Jensen V. Behrana , Javle Milind , Rodon Jordi , Meric-Bernstam Funda 
Published: February 2024

Abstract

Zanidatamab is a bispecific human epidermal growth factor receptor 2 (HER2)-targeted antibody that has demonstrated antitumor activity in a broad range of HER2-amplified/expressing solid tumors. We determined the antitumor activity of zanidatamab in patient-derived xenograft (PDX) models developed from pretreatment or postprogression biopsies on the first-in-human zanidatamab phase I study (NCT02892123). Of 36 tumors implanted, 19 PDX models were established (52.7% take rate) from 17 patients. Established PDXs represented a broad range of HER2-expressing cancers, and in vivo testing demonstrated an association between antitumor activity in PDXs and matched patients in 7 of 8 co-clinical models tested. We also identified amplification of MET as a potential mechanism of acquired resistance to zanidatamab and demonstrated that MET inhibitors have single-agent activity and can enhance zanidatamab activity in vitro and in vivo. These findings provide evidence that PDXs can be developed from pretreatment biopsies in clinical trials and may provide insight into mechanisms of resistance.

Significance:
We demonstrate that PDXs can be developed from pretreatment and postprogression biopsies in clinical trials and may represent a powerful preclinical tool. We identified amplification of MET as a potential mechanism of acquired resistance to the HER2 inhibitor zanidatamab and MET inhibitors alone and in combination as a therapeutic strategy.
This article is featured in Selected Articles from This Issue, p. 695
Information, Coding, and Biological Function: The Dynamics of
Life
Authors: Cartwright Julyan H. E. , Čejková Jitka , Fimmel Elena , Giannerini Simone , Gonzalez Diego Luis , Goracci Greta , Grácio Clara , Houwing-Duistermaat Jeanine , Matić Dragan , Mišić Nataša , Mulder Frans A. A. , Piro Oreste 
Published: February 2024

Abstract
In the mid-20th century, two new scientific disciplines emerged forcefully: molecular biology and information-communication theory. At the beginning, cross-fertilization was so deep that the term genetic code was universally accepted for describing the meaning of triplets of mRNA (codons) as amino acids. However, today, such synergy has not taken advantage of the vertiginous advances in the two disciplines and presents more challenges than answers. These challenges not only are of great theoretical relevance but also represent unavoidable milestones for next-generation biology: from personalized genetic therapy and diagnosis to Artificial Life to the production of biologically active proteins. Moreover, the matter is intimately connected to a paradigm shift needed in theoretical biology, pioneered a long time ago, that requires combined contributions from disciplines well beyond the biological realm. The use of information as a conceptual metaphor needs to be turned into quantitative and predictive models that can be tested empirically and integrated in a unified view. Successfully achieving these tasks requires a wide multidisciplinary approach, including Artificial Life researchers, to address such an endeavour.
Diagnostic accuracy of conventional orthodontic radiographic modalities and cone-beam computed tomography for localization of impacted maxillary canine teeth
Authors: Salari Behzad , Tofangchiha Maryam , Padisar Parviz , Reda Rodolfo , Zanza Alessio , Testarelli Luca 
Published: February 2024

Background: Orthodontic treatment planning for an impacted canine tooth requires accurate information about its position. The aim of this study was to compare the diagnostic accuracy of two conventional orthodontic radiographic modalities with cone-beam computed tomography (CBCT) for localization of impacted maxillary canine teeth. Materials and Methods: Panoramic radiographs, lateral cephalograms, and CBCT scans of 30 patients with unilaterally impacted maxillary canine teeth were retrieved from the archives. Eight expert orthodontists evaluated the parameters related to the location of impacted canine teeth by using panoramic radiographs and lateral cephalograms of patients. After 4 weeks, the same parameters were evaluated on CBCT scans of patients. The diagnostic accuracy of conventional modalities and CBCT was compared with each other and also with the gold standard. Results: The conventional radiographic modalities and CBCT had similar accuracy for assessment of the overall inclination ( p = 0.11), apex morphology ( p = 0.18), and mesiodistal position of the apex ( p = 0.12). CBCT had significantly higher accuracy for determination of incisal tip location ( p = 0.001), labiopalatal ( p = 0.001) and vertical ( p = 0.01) position of the crown tip, minimum bone thickness covering the crown ( p = 0.001), and root resorption of the adjacent tooth ( p = 0.001). Conclusion: The combination of panoramic radiographs and lateral cephalograms was sufficiently accurate to assess some diagnostic parameters such as overall inclination, apex morphology, and mesiodistal apex location of impacted canine teeth.
Otitis media with effusion in adults during the SARS-CoV-2 epidemic
Authors: Zhang Yu , Yang Feifei , He Yanan , Yan Sinan , Bai Yushuang , Jin Yifan , Shi Hui , Liu Jingrui , Zhang Zhanchi , Luan Feng 
Published: February 2024

Objectives The purpose of this study was to investigate the fluctuations in the prevalence of individuals diagnosed with otitis media with effusion (OME) during the SARS-CoV-2 pandemic, while also evaluating the persistence of SARS-CoV-2 in middle ear effusion (MEE) and assessing the effectiveness of tympanocentesis as a treatment modality for OME in this specific period. Methods The total number of outpatients and patients diagnosed with OME in our department was recorded for January 2022 and January 2023. Thirty patients (aged 15–86 years) were categorized into two groups: group A (n = 12), who developed OME during their SARS-CoV-2 infection and group B (n = 18), who experienced OME after the resolution of SARS-CoV-2 infection. All patients underwent otoendoscopic tympanocentesis (without a ventilation tube), where MEE and nasopharyngeal secretions were simultaneously collected for SARS-CoV-2 detection by polymerase chain reaction. The time interval from SARS-CoV-2 infection to tympanocentesis, results of SARS-CoV-2 detection, preoperative and postoperative average hearing threshold, and Eustachian Tube Dysfunction Questionnaire (ETDQ-7) scores were documented. Results The proportion of outpatients with OME in January 2023 was higher than that in January 2022. There were five patients who had positive test results for SARS-CoV-2 on MEE after tympanocentesis. These 5 patients underwent tympanocentesis at a mean of 28 ± 7.28 days following confirmation of SARS-CoV-2 infection. The ETDQ-7 scores of group A exhibited a reduction from 21.85 ± 4.8 to 10.00 ± 4.07 following tympanocentesis, while the ETDQ-7 scores of group B also demonstrated a decrease from 21.22 ± 4.65 to 10.11 ± 3.68 after undergoing tympanocentesis. The tympanocentesis was effective in both groups. Conclusions The study confirmed that the proportion of outpatients with OME in the Clinics of Otolaryngology during the SARS-CoV-2 epidemic increased significantly. SARS-CoV-2 RNA was detectable in MEE of COVID-19-related OME patients. Tympanocentesis was therapeutic for OME during SARS-CoV-2 infection, which facilitated viral clearance in MEE.
A Combined Treatment of BMP2 and Soluble VEGFR1 for the Enhancement of Tendon-Bone Healing by Regulating Injury-Activated Skeletal Stem Cell Lineage
Authors: Wang Linfeng , Wan Liyang , Zhang Tao , Guan Changbiao , Hu Jianzhong , Xu Daqi , Lu Hongbin 
Published: February 2024

Background: Bone morphogenetic protein 2 (BMP2) is an appealing osteogenic and chondrogenic growth factor for promoting tendon-bone healing. Recently, it has been reported that soluble vascular endothelial growth factor (VEGF) receptor 1 (sVEGFR1) (a VEGF receptor antagonist) could enhance BMP2-induced bone repair and cartilage regeneration; thus, their combined application may represent a promising treatment to improve tendon-bone healing. Moreover, BMP2 could stimulate skeletal stem cell (SSC) expansion and formation, which is responsible for wounded tendon-bone interface repair. However, whether the codelivery of BMP2 and sVEGFR1 increases tendon enthesis injury–activated SSCs better than does BMP2 alone needs further research. Purpose: To study the effect of BMP2 combined with sVEGFR1 on tendon-bone healing and injury-activated SSC lineage. Study Design: Controlled laboratory study. Methods: A total of 128 C57BL/6 mice that underwent unilateral supraspinatus tendon detachment and repair were randomly assigned to 4 groups: (1) untreated control group; (2) hydrogel group, which received a local injection of the blank hydrogel at the injured site; (3) BMP2 group, which received an injection of hydrogel with BMP2; and (4) BMP2 with sVEGFR1 group, which received an injection of hydrogel with BMP2 and sVEGFR1. Histology, micro–computed tomography, and biomechanical tests were conducted to evaluate tendon-bone healing at 4 and 8 weeks after surgery. In addition, flow cytometry was performed to detect the proportion of SSCs and their downstream differentiated subtypes, including bone, cartilage, and stromal progenitors; osteoprogenitors; and pro-chondrogenic progenitors within supraspinatus tendon enthesis at 1 week postoperatively. Results: The repaired interface in BMP2 with sVEGFR1 group showed a significantly improved collagen fiber continuity, increased fibrocartilage, greater newly formed bone, and elevated mechanical properties compared with the other 3 groups. There were more SSCs; bone, cartilage, and stromal progenitors; osteoprogenitors; and pro-chondrogenic progenitors in the BMP2 with sVEGFR1 group than that in the other groups. Conclusion: Our study suggests that the combined delivery of BMP2 and sVEGFR1 could promote tendon-bone healing and stimulate the expansion of SSCs and their downstream progeny within the injured tendon-bone interface. Clinical Relevance: Combining BMP2 with sVEGFR1 may be a good clinical treatment for wounded tendon enthesis healing.
Impact of Weight Concern on Post-Cessation Weight Management, Smoking Cessation, and Program Engagement
Authors: Toyon Anjola , Bursac Zoran , Werner Nicole , Krukowski Rebecca A. 
Published: February 2024

Purpose Weight concern is a barrier to smoking cessation. We examined the impact of weight concern on post-cessation weight gain, abstinence and program engagement. Design Randomized-controlled trial. Setting Telephone-based and group-based intervention sessions. Subjects 305 participants were randomized and analyzed. Intervention Participants were randomized to receive a self-guided intervention, a weight loss intervention, or a weight stability intervention prior to all receiving the same smoking cessation intervention. Measures Level of weight concern on three measures, point-prevalence abstinence, weight change, and session attendance at 12 months. Analysis Continuous and discrete outcomes were compared between weight-concerned and non-weight-concerned participants using two-sample t-tests and chi-square tests respectively. Results There were no significant differences in weight change (range: +1.77, −1.91 kg) when comparing weight-concerned and non-weight-concerned participants. Point-prevalence abstinence ranged from 36% to 64%, with no differences by condition based on level of weight concern. There were no significant differences in session attendance by weight concern (Weight sessions: 50–70%, Smoking cessation sessions: 41–56%, Booster sessions: 28–45%). Weight concern, on all measures, significantly decreased between screening and 2 months (after the weight management intervention), for most of the comparisons made overall and by condition. Conclusion It may not be necessary to screen for weight concerns in smoking cessation and/or post-cessation weight management programs, as the trial interventions were beneficial regardless of weight concern.