bluuebunny/crossref_metadata_2025 huggingface dataset:
Docetaxel-oxaliplatin-capecitabine/5-fluorouracil (DOX/F) followed by docetaxel versus oxaliplatin-capecitabine/5-fluorouracil (CAPOX/FOLFOX) in HER2-negative advanced gastric cancers
Authors: Ramaswamy Anant , Bhargava Prabhat , Dubashi Biswajit , Gupta Anuj , Kapoor Akhil , Srinivas Sujay , Shetty Omshree , Jadhav Poonam , Desai Veena , Noronha Vanita , Joshi Amit , Menon Nandini , Patil Vijay M , Mishra Bal Krishna , Sansar Bipinesh , Singh Arpita , Patel Swapnil , Singh Satyendra Narayan , Dhal Ipsita , Vinayak Kunal Ranjan , Pal Vikash , Mandavkar Sarika , Kannan Sadhana , Chaugule Deepali , Patil Rajshree , Parulekar Manali , Nashikkar Chaitali , Ankathi Suman Kumar , Kaushal Rajiv Kumar , Shah Aekta , Ganesan Prasanth , Kayal Smita , Ananthakrishnan Ramesh , Syed Noorzia , Samaddar Debdeep , Kapu Venkatesh , Shah Anokhi , Kaaviya D , Suganiya R , Srinivasan Nirmala Devi , Prabhash Kumar , Ostwal Vikas
Published: July 2024

Background

We evaluated whether the addition of docetaxel (D) to a combination comprising 5-fluorouracil/leucovorin (5-FU/LV) or capecitabine (C) plus oxaliplatin (O) (DOF/DOX) improved overall survival (OS) compared with 6 months of 5-fluorouracil (5-FU) or capecitabine in combination with oxaliplatin (FOLFOX/CAPOX) alone in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas (G/GEJ).

Methods

This study was an investigator-initiated, open-label, multi-institutional, randomized phase III trial in adult patients with HER2-negative advanced G/GEJs. The primary endpoint of the study was a comparison of median OS by Kaplan-Meier method. Next-generation sequencing was performed on tissue.

Results

Of the 324 patients randomly assigned between July 2020 and November 2022, 305 patients were evaluable for analysis (FOLFOX/CAPOX: 156; DOF/DOX: 149). With a median follow-up time of 19.2 months (95% Confidence Interval [CI] = 16.5 months to 21.9 months) for the entire cohort, the median OS was 10.1 months (95% CI = 9.2 to 10.9) for FOLFOX/CAPOX and 8.9 months (95% CI = 7.3 to 10.5) for DOF/DOX, and this difference was not statistically significant (P = .70). An increased proportion of grade 3 or grade 4 neutropenia (21% vs 3%; P < .001) and grade 2/3 neuropathy (17% vs 7%; P = .005) was seen in patients receiving DOF/DOX. Genomic profiling revealed a low incidence of microsatellite instability (1%) and a high incidence of BRCA1 (8.4%) and BRCA2 (7.5%) somatic alterations.

Conclusion

FOLFOX or CAPOX chemotherapy for 6 months remains one of the standards of care in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas, with no additional survival benefit seen with the addition of docetaxel. Genomic profiling of patients revealed a higher than previously known incidence of somatic BRCA alterations, which requires further evaluation.

CTRI (Clinical Trial Registry of India: CTRI/2020/03/023944).
Serial properties, selector proofs and the provability of consistency
Authors: Artemov Sergei
Published: July 2024

The consistency of a theory means that each of its formal derivations $D_{0}, D_{1}, D_{2}, \ldots $ is free of contradictions. For Peano Arithmetic PA, after the standard coding of derivations by numerals, PA-consistency is directly represented by the consistency scheme  $\textsf{Con}^{S}_{\textsf{PA}}$, which is a series of arithmetical statements ‘$n$ is not a code of a derivation of $\ (0=1)$’ for numerals $n=0,1,2,\ldots $. We note that the consistency formula  $\textsf{Con}_{\textsf{PA}}$, $\forall x$ ‘$x$  is not a code of a derivation of $(0=1)$,’ is strictly stronger in PA than PA-consistency and corresponds to some other property, which we call uniform consistency. When studying the provability of consistency in PA we ought to work not with the consistency formula $\textsf{Con}_{\textsf{PA}}$ but rather with the consistency scheme $\textsf{Con}^{S}_{\textsf{PA}}$, which adequately represents PA-consistency. This paper introduces the Hilbert-inspired notion of proof of an infinite series of formulas in a theory and proves PA-consistency in the form $\textsf{Con}^{S}_{\textsf{PA}}$ in PA. These findings show that PA proves its consistency whereas, by Gödel’s second incompleteness theorem, PA cannot prove its uniform consistency.
The effects of sarilumab as monotherapy and in combination with non-methotrexate disease-modifying anti-rheumatic drugs on unacceptable pain in patients with rheumatoid arthritis: A post-hoc analysis of the HARUKA phase 3 study
Authors: Tanaka Yoshiya , Takahashi Toshiya , van Hoogstraten Hubert , Kato Naoto , Kameda Hideto
Published: July 2024

Objectives

To investigate unacceptable pain [UP; visual analogue scale (VAS) >40 mm] and uncontrolled inflammation [C-reactive protein (CRP) ≥1.0 mg/dL] in patients with active rheumatoid arthritis (RA) receiving sarilumab (SAR) as monotherapy or in combination with non-methotrexate conventional synthetic disease-modifying antirheumatic drugs (SAR + csDMARDs).

Methods

In the HARUKA Phase 3 study (NCT02373202), Japanese patients received either SAR monotherapy (n = 61) or SAR + csDMARDs (n = 30). In this post-hoc analysis, changes in the proportions of patients with/without UP and controlled/uncontrolled inflammation were assessed over 52 weeks.

Results

At baseline, 80.3% (49/61) of patients receiving SAR monotherapy had UP and this proportion decreased with treatment to 55.9% (33/59) at Week 4 and 15.5% (9/58) at Week 52. The SAR + csDMARDs group achieved a reduction in UP from 73.3% (22/30) at baseline to 34.5% (10/29) at Week 4 and 0% (0/24) by Week 52. At baseline, 34.4% (21/61) and 50% (15/30) of patients had both UP and uncontrolled inflammation in the SAR monotherapy and SAR + csDMARDs groups; by Week 2, the proportions decreased to 6.6% (4/61) and 3.3% (1/30), respectively; and 0% in both groups by Week 52.

Conclusion

UP and inflammation were reduced in patients with active RA in Japan in both SAR monotherapy and SAR + csDMARDs treatment groups.
Genomic background sequences systematically outperform synthetic ones in de novo motif discovery for ChIP-seq data
Authors: Raditsa Vladimir V , Tsukanov Anton V , Bogomolov Anton G , Levitsky Victor G
Published: July 2024

Efficient de novo motif discovery from the results of wide-genome mapping of transcription factor binding sites (ChIP-seq) is dependent on the choice of background nucleotide sequences. The foreground sequences (ChIP-seq peaks) represent not only specific motifs of target transcription factors, but also the motifs overrepresented throughout the genome, such as simple sequence repeats. We performed a massive comparison of the ‘synthetic’ and ‘genomic’ approaches to generate background sequences for de novo motif discovery. The ‘synthetic’ approach shuffled nucleotides in peaks, while in the ‘genomic’ approach selected sequences from the reference genome randomly or only from gene promoters according to the fraction of A/T nucleotides in each sequence. We compiled the benchmark collections of ChIP-seq datasets for mouse, human and Arabidopsis, and performed de novo motif discovery. We showed that the genomic approach has both more robust detection of the known motifs of target transcription factors and more stringent exclusion of the simple sequence repeats as possible non-specific motifs. The advantage of the genomic approach over the synthetic approach was greater in plants compared to mammals. We developed the AntiNoise web service (https://denovosea.icgbio.ru/antinoise/) that implements a genomic approach to extract genomic background sequences for twelve eukaryotic genomes.
Correlated crustal and mantle melting documents proto-Tibetan Plateau growth
Authors: Li Wei , He Rizheng , Yuan Xiaohui , Schneider Felix , Tilmann Frederik , Guo Zhen , Chen Yongshun John
Published: July 2024

The mechanism that causes the rapid uplift and active magmatism of the Hoh-Xil Basin in the northern Tibetan Plateau and hence the outward growth of the proto-plateau is highly debated, more specifically, over the relationship between deep dynamics and surface uplift. Until recently the Hoh-Xil Basin remained uncovered by seismic networks due to inaccessibility. Here, based on linear seismic arrays across the Hoh-Xil Basin, we present a three-dimensional S-wave velocity (VS) model of the crust and uppermost mantle structure beneath the Tibetan Plateau from ambient noise tomography. This model exhibits a widespread partially molten crust in the northern Tibetan Plateau but only isolated pockets in the south manifested as low-VS anomalies in the middle crust. The spatial correlation of the widespread low-VS anomalies with strong uppermost mantle low-VS anomalies and young exposed magmatic rocks in the Hoh-Xil Basin suggests that the plateau grew through lithospheric mantle removal and its driven magmatism.
Outcome of Corynebacterial Bloodstream Infection in Patients With Cardiac Implantable Electronic Devices: A Brief Report and Systematic Review
Authors: Chesdachai Supavit , Baddour Larry M , Sohail M Rizwan , Palraj Bharath Raj , Madhavan Malini , Tabaja Hussam , McGinnis Michele T , Fida Madiha , Challener Douglas W , DeSimone Daniel C
Published: July 2024

Cardiac implantable electronic device infection in the context of corynebacterial bloodstream infection (BSI) remains poorly understood. From 2012 to 2023 at Mayo Clinic, 4 of 12 patients with corynebacterial BSI had cardiac implantable electronic device infection: 1 patient was diagnosed during a relapsing BSI episode. Undefined source, persistent BSI, and the presence of a prosthetic cardiac valve were common characteristics.
Gang Rule: Understanding and Countering Criminal Governance
Authors: Blattman Christopher , Duncan Gustavo , Lessing Benjamin , Tobón Santiago
Published: July 2024

Criminal groups govern millions worldwide. Even in strong states, gangs resolve disputes and provide security. Why do these duopolies of coercion emerge? Often, gangs fill vacuums of official power, suggesting that increasing state presence should crowd out criminal governance. We show, however, that state and gang rule can be strategic complements. In particular, gangs could minimize seizures and arrests by keeping neighbourhoods orderly and loyal. If true, increasing state presence could increase incentives for gang rule. In Medellín, Colombia, criminal leaders told us they rule to protect drug rents from police. We test gang responses to state presence using a geographic discontinuity. Internal border changes in 1987 assigned blocks to be closer or further from state security for three decades. Gangs exogenously closer to state presence developed more governance over time. They primarily did so in neighbourhoods with the greatest potential drug rents. This suggests new strategies for countering criminal governance.
Association of Cerebral Microbleeds and Risk of Stroke and Mortality in Posterior Circulation Cerebral Infarction
Authors: Wang Yajuan , Sun Xiaoyan , Wu Shasha , Sun Jianxiu , Yang Yuyuan , Luan Moxin , Yu Fei , Zhou Jing , Chi Xiaosa , Zheng Xueping
Published: July 2024

Objective

This study was investigated to determine whether CMBs were associated with the risk of recurrent stroke or all-cause death in patients with acute posterior circulation cerebral infarction.

Methods

A retrospective analysis was conducted on 323 patients with acute posterior circulation cerebral infarction who aged ≥ 45 years and were hospitalized at Qingdao University Affiliated Hospital from January 1, 2016 to December 31, 2020. Patients were divided into different CMBs groups according to the presence, number and distribution of CMBs. Occurrence of stroke and death was recorded during follow-up. We drew Kaplan Meier survival curves and constructed Cox proportional hazards regression models based on different CMBs groups and clinical outcomes.

Results

A total of 323 patients were enrolled in our study, and 138 (42.72%) had CMBs. During a median follow-up of 1357 days, 87 (26.94%) experienced recurrent stroke or death. ≥5 CMBs (HR 1.723; 95% CI 1.021-2.907; P=0.041) and lobar CMBs (HR 2.312; 95% CI 1.204-4.441; P=0.012) were independent predictors associated with the composite risk of recurrent stroke and all-cause death. All CMBs statuses were not significantly correlated with the risk of recurrent stroke. The presence of CMBs (HR 3.358; 95% CI 1.259-8.954; P=0.015), ≥ 5 CMBs (HR 5.290; 95% CI 1.599-17.499; P=0.006) and deep CMBs (HR 3.265; 95% CI 1.003-10.628; P=0.049) were all independent factors associated with all-cause death.

Conclusions

In patients with acute posterior circulation cerebral infarction, ≥5 CMBs and lobar CMBs may increase the risk of poor clinical outcome (the composite of recurrent stroke and all-cause death). Furthermore, the presence CMBs, ≥ 5 CMBs and deep CMBs all independently may increase the risk of all-cause death.
Early prediction of ovarian cancer risk based on real world data
Authors: de la Oliva Víctor , Esteban-Medina Alberto , Alejos Laura , Muñoyerro-Muñiz Dolores , Villegas Román , Dopazo Joaquín , Loucera Carlos
Published: July 2024

This study presents the development of an early prediction model for high-grade serous ovarian cancer (HGSOC) using real-world data from the Andalusian Health Population Database (BPS), containing electronic health records (EHR) of over 15 million patients. Leveraging the extensive data availability, the model aims to identify individuals at high risk of HGSOC without the need for specific tumor markers or prior stratification into risk groups. Utilizing an Explainable Boosting Machine (EBM) algorithm, the model incorporates diverse clinical variables including demographics, chronic diseases, symptoms, blood test results, and healthcare utilization patterns. The model was trained and validated using a total of 3,088 HGSOC patients diagnosed between 2018 and 2022 along with 114,942 controls of similar characteristics, to emulate the prevalence of the disease, achieving a sensitivity of 0.65 and a specificity of 0.85. This study underscores the importance of using patient data from the general population, demonstrating that effective early detection models can be developed from routinely collected healthcare data. The approach addresses limitations of traditional screening methods by providing a cost-effective and broadly applicable tool for early cancer detection, potentially improving patient outcomes through timely interventions. The interpretability of the early prediction model also offers insights into the most significant predictors of cancer risk, further enhancing its utility in clinical settings.
CFO: Calibration-Free Odds Bayesian Designs for Dose Finding in Clinical Trials
Authors: Fang Jialu , Wang Wenliang , Yin Guosheng
Published: July 2024

The calibration-free odds type (CFO-type) of designs, as data-driven decision-making Bayesian approaches, leverage historical cumulative data across various dose levels, primarily aiming at identifying the maximum tolerated dose (MTD). Inheriting the ideas from game theory or “tug-of-war”, CFO mimics the games of force: one pushes the dose down while the other pushes it up. Extensive simulations validate that CFO-type designs maintain an optimal balance between efficiency and safety in MTD identification, with performance metrics that are comparable to, or occasionally surpass the state-of-the-art methods. This article primarily introduces the R packageCFOfor implementing and assessing CFO-type designs in phase I clinical trials. Besides, we propose integrating the mechanism of exploration and exploitation from reinforcement learning into the CFO design, leading to a novel approach: the randomized CFO (rCFO) design. TheCFOpackage encompasses various variants tailored to accommodate different scenarios. Beyond the fundamental CFO design, these include the two-dimensional CFO (2dCFO) designed for drug-combination trials, accumulative CFO (aCFO) for accruing all dose information, time-to-event CFO (TITE-CFO), and fractional CFO (fCFO) which are developed to specifically address late-onset toxicity. Moreover, hybrid designs such as TITE-aCFO and f-aCFO, which integrate both late-onset toxicity and all dose information for decision making, are also included.CFOprovides a robust set of functions used for determining subsequent cohort doses, selecting the MTD, and conducting simulations to evaluate design operating characteristics. The properties and results are presented to trial investigators through simple textual and graphical outputs. The user-friendly interface, adaptability to various design considerations, and the comprehensive implementation of CFO-type designs positionCFOas a noteworthy tool for phase I clinical trials.
Causes of excess deaths in the US relative to other wealthy nations, 1999-2020: a population autopsy
Authors: Bor Jacob , Raquib Rafeya , Himmelstein David , Woolhandler Steffie , Stokes Andrew C.
Published: July 2024

Importance

The US has higher mortality rates than other wealthy nations.

Objective

To determine causes of death responsible for excess mortality in the US compared to other wealthy nations and how the causes involved in this survival gap have changed over time.

Design

Repeat cross-sectional study, 1999 to 2020.

Setting

United States and 12 other wealthy nations.

Participants

All residents.

Exposures

Residing in the US versus other wealthy nations.

Main outcome and measures

Excess US mortality in each year due to specific causes of death using data from the World Health Organization Mortality Database. Differences between the US and other wealthy nations were quantified for each cause of death as: (1) the number of excess US deaths (i.e., deaths that would have been averted if US death rates equaled the average rates of other wealthy nations); (2) years of life lost (YLL) resulting from excess US deaths; and (3) the ratio of observed deaths to expected deaths if US mortality rates equaled the average of other wealthy nations.

Results

10,856,851 excess US deaths occurred between 1999 and 2020. In 2019, prior to the COVID-19 pandemic, there were 637,682 excess US deaths, with leading causes including circulatory diseases (41% of total), mental and nervous system disorders (25%), diabetes, renal, and metabolic diseases (15%), drug poisonings, alcohol-related deaths, and suicide (13%), respiratory disease (12%), and transportation accidents (5%). Over two decades, excess US deaths due to drug poisonings, alcohol and suicide increased from -5,937 in 1999 to 109,015 in 2020. In 2019, deaths from drug poisonings were 6.7 times higher in the US than in peer countries. Circulatory mortality accounted for the largest absolute number of excess US deaths in nearly every year. In 2020, one in 5 excess US deaths were attributed to COVID-19.

Conclusions and Relevance

The US had substantially higher death rates than other wealthy nations between 1999 and 2020, despite having similar access to advanced medical technology. Many of these excess US deaths could likely be avoided by adopting health and social policies that have benefited peer countries.

KEY POINTS

Question

What causes of death are responsible for the survival gap between the US and other wealthy nations?

Findings

Between 1999 and 2020, 10,856,851 US deaths would have been averted if the US had mortality rates equal to the average of peer countries. Circulatory diseases were the leading cause of excess deaths, although deaths due to drugs, alcohol, and suicide increased the most during the study period. Mental and nervous system disorders, diabetes, renal, and metabolic diseases, and transportation accidents were also major contributors.

Meaning

The causes of death responsible for the US survival gap suggest areas for policy intervention.
Sex-modulated association between thyroid stimulating hormone and informant-perceived anxiety in non-depressed older adults: prediction models and relevant cutoff value
Authors: Hallab Asma ,   Alzheimer’s Disease Neuroimaging Initiative
Published: July 2024

Highlights

Lower TSH levels predicted higher odds of anxiety in non-depressed older adults.

The association between TSH and anxiety was significant in older males but not in older females.

TSH level corresponding to 2.4 µIU/mL was a significant cutoff value in this association, under which thyroid function predicted significantly higher odds of anxiety in older males.

Only in older males, but not older females, TSH levels were significantly lower in those with anxiety than in those without.

Introduction

The aim of this study was to assess the association between thyroid function and perceived anxiety in non-depressed older adults.

Methods

Non-depressed Alzheimer’s Disease Neuroimaging Initiative participants with complete Thyroid Stimulating Hormone (TSH) and neuropsychiatric inventory (NPI/NPI-Q) were included. The association between anxiety and thyroid function was assessed by logistic regression and sex stratification. Restricted cubic splines were applied to evaluate non-linearity in the association.

Results

The median age of 2,114 eligible participants was 73 years (68-78), 1,117 (52.84%) were males, and the median TSH was 1.69µIU/mL. There was a significant association between TSH and informant-perceived anxiety in the total study population (ORModel1=0.86, 95%CI 0.76-0.97, p=0.011), even after adjusting for bio-demographical (adj.ORModel2=0.85, 95%CI 0.75-0.96, p=0.007), and socio-cognitive confounders (adj.ORModel3=0.84, 95%CI 0.73-0.96, p=0.009). Sex-stratification showed similar significant results in all models only in males (ORModel1-male=0.71, 95%CI: 0.58-0.85,pModel1-male<0.001). In the general population and males, a TSH value of 2.4µIU/dL was a significant cutoff under which anxiety odds were significantly high, even after adjusting for confounders.

Conclusions

The sex-dependent association between TSH levels and perceived anxiety in non-depressed older adults is a novel finding that has to be further explored for a better understanding of the underlying neurobehavioral biology.

Abstract Figure
Patterns of Immune Dysregulation in Bipolar Disorder
Authors: Argue Benney M.R. , Casten Lucas G. , McCool Shaylah , Alrfooh Aysheh , Gringer Richards Jenny , Wemmie John A. , Magnotta Vincent A. , Williams Aislinn J. , Michaelson Jacob , Fiedorowicz Jess G. , Scroggins Sabrina M. , Gaine Marie E.
Published: July 2024

Background

Bipolar disorder is a debilitating mood disorder associated with a high risk of suicide and characterized by immune dysregulation. In this study, we used a multi-faceted approach to better distinguish the pattern of dysregulation of immune profiles in individuals with BD.

Methods

We analyzed peripheral blood mononuclear cells (bipolar disorder N=39, control N=30), serum cytokines (bipolar disorder N=86, control N=58), whole blood RNA (bipolar disorder N=25, control N=25), and whole blood DNA (bipolar disorder N=104, control N=66) to identify immune-related differences in participants diagnosed with bipolar disorder compared to controls.

Results

Flow cytometry revealed a higher proportion of monocytes in participants with bipolar disorder together with a lower proportion of T helper cells. Additionally, the levels of 18 cytokines were significantly elevated, while two were reduced in participants with bipolar disorder. Most of the cytokines altered in individuals with bipolar disorder were proinflammatory. Forty-nine genes were differentially expressed in our bipolar disorder cohort and further analyses uncovered several immune-related pathways altered in these individuals. Genetic analysis indicated variants associated with inflammatory bowel disease also influences bipolar disorder risk.

Discussion

Our findings indicate a significant immune component to bipolar disorder pathophysiology and genetic overlap with inflammatory bowel disease. This comprehensive study supports existing literature, whilst also highlighting novel immune targets altered in individuals with bipolar disorder. Specifically, multiple lines of evidence indicate differences in the peripheral representation of monocytes and T cells are hallmarks of bipolar disorder.
Genome-Wide Association Study of Metabolic Traits in the DuckweedSpirodela polyrhiza
Authors: Höfer Martin , Schäfer Martin , Wang Yangzi , Wink Samuel , Xu Shuqing
Published: July 2024

The exceptionally high growth rate and high contents of flavonoids make the giant duckweedSpirodela polyrhiza(L.) Schleid. (Arales: Lemnaceae) an ideal organism for food production and metabolic engineering. To facilitate this, identification of the genetic basis underlying growth and metabolic traits is essential. Here, we characterized the genetics underpinning the growth and contents of 42 metabolites inS. polyrhizausing a genome-wide association (GWA) approach. We found that biomass positively correlates with contents of many free amino acids, including L-Glutamine, L-Tryptophane and L-Serine, but negatively correlates with many specialized metabolites, such as flavonoids. GWA analysis showed that several candidate genes were simultaneously associated with several metabolic traits, qualifying them as targets for growth manipulation and metabolic engineering. Together, this study provides insights into the metabolic diversity ofS. polyrhizaand its underlying genetic architecture, paving the way for industrial applications of this plant via targeted breeding or genetic engineering.
FZD2 inhibits YAP and prevents cell cycle reentry in adult murine cardiomyocytes
Authors: Bisson Joseph A. , Quijada Pearl J. , Wang Yves T. , Lighthouse Janet K. , Helt Jay Christian , Kim Eugene , Morrisey Edward E. , Brookes Paul S. , Small Eric M. , Cohen Ethan D.
Published: July 2024

Rationale

Fully differentiated cardiomyocytes (CMs) are post-mitotic and cannot repopulate damaged tissue after myocardial infarction (MI). Understanding the mechanisms preventing CM proliferation or promoting their survival after injury may lead to treatment strategies for MI. While the effects of canonical WNT/β-catenin signaling in adult CMs have been examined, roles for non-canonical WNT signaling in cardiac homeostasis and repair remain unexplored.

Objective

To determine the function of the non-canonical WNT receptor frizzled 2 (FZD2) in adult cardiac homeostasis and injury.

Methods and Results

FZD2 was deleted from the CMs of adult mice to investigate its role in myocardial homeostasis.Fzd2conditional knockout (CKO) mice had cardiomegaly but not hypertrophy. FZD2-deficient CMs expressed proliferation and cytokinesis markers, suggesting that they have increased proliferation potential. FZD2-deletion caused the accumulation of β-catenin. However, β-catenin localized to the membranes of FZD2-deficient CMs and did not activate target gene expression. Instead, the YES-associated protein (YAP) regulated genesv-myc avian myelocytomatosis viral oncogene 1 (Mycl), andB cell leukemia/lymphoma 2 (Bcl2l1)were upregulated inFzd2CKO CMs relative to controls. Knockdown of FZD2 increased YAP activity in neonatal ventricular CMs (NVCMs), while overexpressing FZD2 inhibited YAP. Neither β-catenin knockdown nor mutating the large tumor suppressor 1 and 2 (LATS1/2) target site on YAP blocked the effects of FZD2 on YAP in NVCMs, suggesting that FZD2 utilizes different effectors than canonical WNT and Hippo signaling.Fzd2CKO and control mice were subjected to MI to determine if FZD2-deletion affects cardiac repair. While ischemia and necrosis were similar 24 hours post MI,Fzd2CKO mice had better cardiac function and less scarring than controls.

Conclusions

FZD2 reduces YAP activity and prevents adult murine CMs from reentering the cell cycle. FZD2-deletion improves heart function and reduces scarring in mice after MI, implicating FZD2 as a target for pharmacological intervention.
Equine piroplasmosis in different geographical areas in France: prevalence heterogeneity of asymptomatic carriers and low genetic diversity ofTheileria equiandBabesia caballi
Authors: Jouglin M , Bonsergent C , de la Cotte N , Mège M , Bizon C , Couroucé A , Lallemand E , Lemonnier L.C. , Leblond A , Leroux A , Marano I , Muzard A , Quéré E , Toussaint M , Agoulon A , Malandrin L
Published: July 2024

Equine piroplasmosis is a worldwide tick-borne disease caused by the protozoan parasitesTheileria equiandBabesia caballi, with significant economic and sanitary consequences. It can also limit the export of infected horses to piroplasmosis-free countries. These two parasites are genetically variable, with greater diversity observed inT. equi. This variability can potentially impact diagnostic accuracy.

Our study aimed to evaluate the frequency of asymptomatic carriers of these parasites in France and describe the circulating genotypes. We used a species-specific nested PCR protocol targeting the 18S small subunit (SSU) rRNA gene and subsequent amplicon sequencing on blood samples collected from 566 asymptomatic horses across four National Veterinary Schools.

The carrier frequency varied considerably, ranging from 18.7% around Paris (central-north) to 56.1% around Lyon (southeast), with an overall prevalence of 38.3%.T. equicarriers were ten times more frequent (91.7%, 209/228 isolates) compared toB. caballicarriers (8.8%, 19/228 isolates). Notably,T. equicarrier frequency was significantly lower in the northern region (Ile de France) compared to the southeastern regions. Interestingly, a strong correlation was observed between the frequencies of asymptomatic carriers and reported cases of acute piroplasmosis across all four geographic areas. Neither gender (female, gelding, or stallion) nor horse age showed a significant effect on the frequency of asymptomatic carriers. In areas with the highest carrier frequency, a substantial proportion of horses (22.2% to 37.5%) carriedT. equibefore the age of three, indicating high infection pressure.

Genotyping of 201T. equiisolates revealed a predominance of genotype E (98%), with only a few isolates belonging to genotype A (2%). Notably, two of the four genotype A isolates were detected in horses originating from Spain. All 19B. caballiisolates belonged to the most common genotype A of this species.

The discussion section explores the link between these results, the tick distribution and abundance, and the frequency of detection ofT. equiandB. caballiin febrile cases attributed to piroplasmosis.
A multicellular actin star network underpins epithelial organization and connectivity
Authors: Amlan Barai , Matis Soleilhac , Wang Xi , Shao-Zhen Lin , Marc Karnat , Elsa Bazellières , Sylvie Richelme , Dominique Berrebi , Frank Rümmele , Manuel Théry , Jean-François Rupprecht , Delphine Delacour
Published: July 2024

Epithelial tissues serve as physical barriers against various external pressures yet remarkably maintain structural stability. Various cellular apparatus including bicellular junction and actomyosin network contribute to the epithelial integrity, packing and remodelling. Although their role in morphogenetic and mechanical processes have been extensively studied during embryogenesis and disease development, their synergistic effects in maintaining tissue organization and connection remain poorly understood. In this study, we discovered a tissue-scale actomyosin network connected through bicellular junctions and manifested in the villi of adult murine intestinal tissue. Later we reproduced such supracellular structure in the differentiated compartment ofex vivo intestinal epithelium model. The self-organized actomyosin networks comprised individual actin nodes in each hexagonal cell at the epithelial base with six radial actin branches, presenting an ‘actin star’ unit. The repeated units were connected through the bicellular junctions, forming a large, multicellular array covering the differentiated domains. Functionally, actin stars contribute to epithelial morphological stability by maintaining cell hexagonality and packing, thereby preserving the solid-like order of the epithelium. Laser ablation experiments validate a modified vertex theoretical model that connects the emergence of such solid-like order to the onset of tension along the actin star branches. Actin stars also acted as locks at the basal side minimizing protrusive activity in the epithelial layer, hindering cell migration and disorganization of the epithelial tissue. The large actomyosin array also enhanced the long-range connectivity that ensure overall tissue integrity. Altogether, the supracellular actin star network constitutes a basal biomechanical apparatus coordinating epithelial tissue stability and organization.
Fully Automated MRI-based Analysis of the Locus Coeruleus in Aging and Alzheimer’s Disease Dementia using ELSI-Net
Authors: Dünnwald Max , Krohn Friedrich , Sciarra Alessandro , Sarkar Mousumi , Schneider Anja , Fliessbach Klaus , Kimmich Okka , Jessen Frank , Rostamzadeh Ayda , Glanz Wenzel , Incesoy Enise I. , Teipel Stefan , Kilimann Ingo , Goerss Doreen , Spottke Annika , Brustkern Johanna , Heneka Michael T. , Brosseron Frederic , Lüsebrink Falk , Hämmerer Dorothea , Düzel Emrah , Tönnies Klaus , Oeltze-Jafra Steffen , Betts Matthew J.
Published: July 2024

INTRODUCTION

The Locus Coeruleus (LC) is linked to the development and pathophysiology of neurodegenerative diseases such as Alzheimer’s Disease (AD). Magnetic Resonance Imaging based LC features have shown potential to assess LC integrity in vivo.

METHODS

We present a Deep Learning based LC segmentation and feature extraction method: ELSI-Net and apply it to healthy aging and AD dementia datasets. Agreement to expert raters and previously published LC atlases were assessed. We aimed to reproduce previously reported differences in LC integrity in aging and AD dementia and correlate extracted features to cerebrospinal fluid (CSF) biomarkers of AD pathology.

RESULTS

ELSI-Net demonstrated high agreement to expert raters and published atlases. Previously reported group differences in LC integrity were detected and correlations to CSF biomarkers were found.

DISCUSSION

Although we found excellent performance, further evaluations on more diverse datasets from clinical cohorts are required for a conclusive assessment of ELSI-Nets general applicability.

Highlights

thorough evaluation of a fully automatic LC segmentation method termed ELSI-Net in aging and AD dementia

ELSI-Net outperforms previous work and shows high agreement with manual ratings and previously published LC atlases

ELSI-Net replicates previously shown LC group differences in aging and AD

ELSI-Net’s LC volume correlates with CSF biomarkers of AD pathology

RESEARCH IN CONTEXT

Systematic Review:The authors reviewed the literature using traditional sources (e.g. Pubmed, Google Scholar). Although there are several publications introducing semi-automatic methods for LC segmentation, the application of Deep Learning methods is underexplored. To the best of our knowledge, this is the first paper using a Deep Learning based approach for automated LC segmentation in AD dementia.

Interpretation:Our work introduces and evaluates an improved automatic, Deep Learning based LC segmentation and analysis approach. The results suggest a very high potential for practical applicability, e.g. in large-scale clinical studies for neurodegenerative diseases.

Future Directions:ELSI-Net can be used to assess LC integrity on large- or small-scale studies in Alzheimer’s Disease dementia. To ensure robust performance, ELSI-Net should be further evaluated in larger, more diverse datasets comprising varying LC MRI protocols and clinical populations.
Evidence of centromeric histone 3 chaperone involved in DNA damage repair pathway
Authors: Agarwal Prakhar , Ghosh Santanu Kumar
Published: July 2024

The centromeric protein-A (CENP-A) is an evolutionary conserved histone H3 variant that marks the identity of the centromeres. Several mechanisms regulate the centromeric deposition of CENP-A as its mislocalization causes erroneous chromosome segregation, leading to aneuploidy-based diseases, including cancers. The most crucial deposition factor is a CENP-A specific chaperone, HJURP (Scm3 in budding yeast), which specifically binds to CENP-A. However, the discovery of HJURP as a DDR (DNA damage repair) protein and evidence of its binding to Holliday junctions in vitro indicate a CENP-A-deposition-independent role of these chaperones. In this study, using budding yeast, we demonstrate that Scm3 is crucial for the DDR pathway asscm3cells are sensitive to DNA damage. We further observe that thescm3mutant interacts with therad52DDR mutant and is compromised in activating DDR-mediated arrest. We demonstrate that Scm3 associates with the DNA damage sites and undergoes posttranslational modifications upon DNA damage. Overall, from this report and earlier studies on HJURP, we conclude that DDR functions of CENP-A chaperones are conserved across eukaryotes. Thus, the revelation that these chaperones confer genome stability in more than one pathway has clinical significance.
Limiting the impact of protein leakage in single-cell proteomics
Authors: Leduc Andrew , Xu Yanxin , Shipkovenska Gergana , Dou Zhixun , Slavov Nikolai
Published: July 2024

Limiting artifacts during sample preparation can significantly increase data quality in single-cell proteomics experiments. Towards this goal, we characterize the impact of protein leakage by analyzing thousands of primary single cells that were prepared either fresh immediately after dissociation or cryopreserved and prepared at a later date. We directly identify permeabilized cells and use the data to define a signature for protein leakage. We use this signature to build a classifier for identifying damaged cells that performs accurately across cell types and species.
Nucleotide dependency analysis of DNA language models reveals genomic functional elements
Authors: Tomaz da Silva Pedro , Karollus Alexander , Hingerl Johannes , Galindez Gihanna , Wagner Nils , Hernandez-Alias Xavier , Incarnato Danny , Gagneur Julien
Published: July 2024

Deciphering how nucleotides in genomes encode regulatory instructions and molecular machines is a long-standing goal in biology. DNA language models (LMs) implicitly capture functional elements and their organization from genomic sequences alone by modeling probabilities of each nucleotide given its sequence context. However, using DNA LMs for discovering functional genomic elements has been challenging due to the lack of interpretable methods. Here, we introduce nucleotide dependencies which quantify how nucleotide substitutions at one genomic position affect the probabilities of nucleotides at other positions. We generated genome-wide maps of pairwise nucleotide dependencies within kilobase ranges for animal, fungal, and bacterial species. We show that nucleotide dependencies indicate deleteriousness of human genetic variants more effectively than sequence alignment and DNA LM reconstruction. Regulatory elements appear as dense blocks in dependency maps, enabling the systematic identification of transcription factor binding sites as accurately as models trained on experimental binding data. Nucleotide dependencies also highlight bases in contact within RNA structures, including pseudoknots and tertiary structure contacts, with remarkable accuracy. This led to the discovery of four novel, experimentally validated RNA structures in Escherichia coli. Finally, using dependency maps, we reveal critical limitations of several DNA LM architectures and training sequence selection strategies by benchmarking and visual diagnosis. Altogether, nucleotide dependency analysis opens a new avenue for discovering and studying functional elements and their interactions in genomes.
The effect of regional factors on energy poverty
Authors: Jové-LLopis Elisenda , Trujillo-Baute Elisa
Published: July 2024

Purpose

Within the framework of EU policies and measures to develop a just and fair green energy transition model. This paper aims to offer valuable insights into a paramount concern not so well debated in the literature, i.e. the spatial variation of energy poverty.

Design/methodology/approach

This empirical analysis investigates the regional variation of energy poverty we draw on a sample of more than 300,000 Spanish households, extracted from the Spanish Household Budget Survey (HBS) for the period 2006–2022. To characterize the probability of a household finding itself in a situation of energy poverty the authors use a discrete choice univariate probit model.

Findings

The results confirm that energy poverty is a phenomenon that is asymmetrically distributed across Spain, and mainly occurs in un-densely populated regions. In addition, the findings demonstrate that the incidence of energy poverty drivers is highly heterogeneous across regions.

Research limitations/implications

The paper ends with some recommendations for policymakers suggesting that countries need to design an energy poverty policy for the households that jointly pursue both a correct identification of vulnerable groups and a match with the type of measure to the characteristics of each region.

Originality/value

This study enhances previous research by considering the case of areas at a lower level of aggregation (i.e. on the NUTS two regions in Spain called autonomous communities) and offers the opportunity to tailor policies to those regions most in need. Furthermore, to provide a more realistic picture of the complex phenomenon of energy poverty, the authors use the information for the period 2006–2022 differentiating by economic micro-cycle. This timespan allows the authors to understand the dynamics of energy poverty in periods of economic crisis, including the effects of the 2008 crisis and the present global energy crisis.
CC-index is a scite-based enhancement of citation metrics
Authors: Gonmei Thuanthailiu , Ravikumar S. , Gayang Fullstar Lamin
Published: July 2024

Purpose

The purpose of this study is to gain insight into how citations are distributed and concentrated in the introduction, methods, discussion, results and other sections of journal articles to determine which section has received the most citations and whether the citation concentration score affects how articles rank.

Design/methodology/approach

The present study uses scite.ai and the Dimensions database to emphasize the significance of including multiple in-text citations in evaluating the impact and quality of journal publications. The study has two approaches: paper-based and author-based.

Findings

The study provides empirical insights into how variations in ranking are observed when citation concentration is considered in the evaluation process. It also suggests that in-text citations be used as an evaluation criterion or aspect for assessing the impact and quality of journals, publications and authors.

Originality/value

This study underscores the importance of considering citation concentration when evaluating journal articles. To assess highly cited articles, it suggests using the CC-index method, which is based on scite.ai.
Examining the influence of gender equality in HRMP on job performance: the mediating role of job satisfaction
Authors: Taamneh Mohammad M. , Al-Okaily Manaf , Barhem Belal , Taamneh Abdallah M. , Alomari Ziyad Saleh
Published: July 2024

Purpose

The purpose of this study is to investigate the impact of gender equality in human resource management practices (HRMP) on job performance in educational hospitals in Jordan. This paper also examines the role of job satisfaction as a mediator between gender equality in HRMP and job performance.

Design/methodology/approach

A quantitative research approach with an online questionnaire was used to collect data from 231 participants at educational hospitals.

Findings

The findings showed that gender equality in HRMP was positively associated with job performance. In addition, the findings found a significant positive effect of gender equality in HRM on job satisfaction. Finally, the findings indicated that job satisfaction mediates the relationship between gender equality in HRMP and job performance.

Originality/value

This study provided theoretical and practical insights on the issue of discrimination against women, representing a model of developing countries, especially in the Middle East.
Who are the key figures in Grand Tours cycling events publications? A systematic review of main themes
Authors: Gholampour Behzad , Noruzi Alireza , Elahi Alireza , Barranco Gil David , Gholampour Sajad
Published: July 2024

Purpose

The purpose of this study is to draw a scientific map of the Grand Tours cycling as part of the growing research field in this field at the global level. This study also identifies the components of scientific production in this field along with their collaboration patterns.

Design/methodology/approach

With the aim of achieving a comprehensive and deep understanding of the studies related to the Grand Tour, this research aims to address the existing gaps and provide a comprehensive summary of these scholarly works. To achieve this goal, the authors used a systematic and scientometric combination method, analyzing studies from the past half century (1970–2022).

Findings

The research findings reveal that scientific studies related to cycling events exhibit a geographical concentration within the continent of Europe, surpassing other continents. Notably, Spain, the USA, the UK and Italy emerge as pioneers in this field of inquiry. The main themes identified in these studies encompass cycling, the Tour de France, performance, professional roa cycling, heart rate, endurance, doping and power output.

Practical implications

This research, along with other systematic studies, contributes to the existing literature in this field by providing both quantitative and qualitative data. Additionally, the study serves as a foundation for identifying active and influential countries, institutions and authors in this domain. Such insights are highly effective in establishing scientific focal points in this field.

Originality/value

This study, in conjunction with the introduction of key figures in mega cycling event research, sheds light on the thematic areas explored within these studies. Notably, it is the sole study that has illuminated hidden facets of this field using scientometric and systematic methods.
Effect of curvature on bubble dynamics and associated heat transfer characteristics for nucleate pool boiling from a hydrophilic curved surface
Authors: Sharma Abhishek Kumar , Tiwari Shaligram
Published: July 2024

Purpose

This paper aims to carry out numerical study on growth of a single bubble from a curved hydrophilic surface, in nucleate pool boiling (NPB). The boiling performance associated with NPB on a curved surface has been analyzed in contrast to a plane surface.

Design/methodology/approach

Commercial software ANSYS Fluent 2021 R1 has been used with its built-in feature of interface tracking based on volume of fluid method. For water as the working fluid, the effect of microlayer evaporation underneath the bubble base has been included with the help of user-defined function. The phase change behavior at the interface of vapor bubble has been modeled by using “saturated-interface-volume” phase change model.

Findings

An interesting outcome of the present study is that the bubble departure gets delayed with increase in curvature of the heating surface. Wall heat flux is found to be higher for a curved surface as compared to a plane surface. Effect of wettability on the time for bubble growth is relatively more for the curved surface as compared to that for a plane surface.

Originality/value

Effect of surface curvature has been investigated on bubble dynamics and also on temporal variation of heat flux. In addition, the impact of surface wettability along with the surface curvature has also been analyzed on bubble morphology and spatial variation of heat flux. Furthermore, the influence of wall superheat on the bubble growth and also the wall heat flux has been studied for fixed angle of contact and varying curvature.