bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Human Intermediate Prolactin Receptor I-tail Contributes Breast Oncogenesis by Targeting Ras/MAPK Pathway
Authors: Shen Shanwei , Radhakrishnan Senthil K , Harrell J Chuck , Puchalapalli Madhavi , Koblinski Jennifer , Clevenger Charles 
Published: May 2024

Abstract
Prolactin and its receptor (PRLr) in humans are significantly involved in breast cancer pathogenesis. The intermediate form of human PRLr (hPRLrI) is produced by alternative splicing and has a novel 13 amino acid tail (“I-tail”) gain. hPRLrI induces significant proliferation and anchorage-independent growth of normal mammary epithelia in vitro when coexpressed with the long form hPRLr (hPRLrL). hPRLrL and hPRLrI coexpression is necessary to induce the transformation of mammary epithelia in vivo. The I-tail is associated with the ubiquitin-like protein neural precursor cell expressed developmentally downregulated protein 8. Treatment with the neural precursor cell expressed developmentally downregulated protein 8-activating enzyme inhibitor pevonedistat resulted in increased hPRLrL and the death of breast cancer cells. The goal of this study was to determine the function of the hPRLrI I-tail in hPRLrL/hPRLrI-mediated mammary transformation. hPRLrL/hPRLrI and hPRLrL/hPRLrIΔ13 (I-tail removal mutant) were delivered to MCF10AT cells. Cell proliferation was decreased when hPRLrI I-tail was removed. I-tail deletion decreased anchorage-independent growth and attenuated cell migration. The I-tail was involved in Ras/MAPK signaling but not PI3K/Akt signaling pathway as shown by western blot. I-tail removal resulted in decreased hPRLrI stability. RNA-sequencing data revealed that I-tail removal resulted in differential gene expression induced by prolactin. Ingenuity Pathway Analysis revealed that the activity of ERK was attenuated. Treatment of breast cancer cells with ERK1/2 inhibitor ulixertinib resulted in decreased colony-forming ability and less proliferation. These studies suggest that the hPRLrI I-tail contributed to breast oncogenesis and may be a promising target for the development of new breast cancer therapies.
Functional Analysis of a Novel HNF4A Variant Identified in a Patient With MODY1
Authors: Morikawa Shuntaro , Ko Hui Ling , Ren Ee Chee , Hara Kazuya , Kaneko Naoya , Hishimura Nozomi , Nakamura Akie , Manabe Atsushi 
Published: May 2024

Abstract

Context
HNF4A–maturity-onset diabetes of the young (MODY1) is a relatively rare subtype of monogenic diabetes caused by loss of function of the HNF4A gene, which encodes the transcription factor HNF4α. HNF4α is known to form heterodimers, and the various combinations of isoforms that make up these heterodimers have been reported to result in a diversity of targeted genes. However, the function of individual HNF4α variant isoforms and the heterodimers comprising both wild-type (WT) and variant HNF4α have not yet been assessed.

Objective
In this study, we analyzed the functional consequence of the HNF4A D248Y variant in vitro.

Methods
We investigated the case of a 12-year-old Japanese girl who developed diabetes at age 11 years. Genetic sequencing detected a novel heterozygous missense HNF4A variant (c.742G &gt; T, p.Asp248Tyr; referred as “D248Y”) in the patient and her relatives who presented with diabetes.

Results
Although the WT HNF4α isoforms (HNF4α2, HNF4α3, HNF4α8, HNF4α9) enhanced the INS gene promoter activity in HepG2 cells, the promoter activity of D248Y was consistently low across all isoforms. The presence of D248Y in homodimers and heterodimers, comprising either HNF4α8 or HNF4α3 or a combination of both isoforms, also reduced the INS promoter activity in Panc-1 cells.

Conclusion
We report the clinical course of a patient with HNF4A-MODY and the functional analysis of novel HNF4A variants, with a focus on the isoforms and heterodimers they form. Our results serve to improve the understanding of the dominant-negative effects of pathogenic HNF4A variants.
Na,K-ATPase activity promotes macropinocytosis in colon cancer via Wnt signaling
Authors: Tejeda-Muñoz Nydia , Azbazdar Yagmur , Sosa Eric A. , Monka Julia , Wei Pu-Sheng , Binder Grace , Mei Kuo-Ching , Kurmangaliyev Yerbol Z. , De Robertis Edward M. 
Published: May 2024

ABSTRACT
Recent research has shown that membrane trafficking plays an important role in canonical Wnt signaling through sequestration of the β-catenin destruction complex inside multivesicular bodies (MVBs) and lysosomes. In this study, we introduce Ouabain, an inhibitor of the Na,K-ATPase pump that establishes electric potentials across membranes, as a potent inhibitor of Wnt signaling. We find that Na,K-ATPase levels are elevated in advanced colon carcinoma, that this enzyme is elevated in cancer cells with constitutively activated Wnt pathway and is activated by GSK3 inhibitors that increase macropinocytosis. Ouabain blocks macropinocytosis, which is an essential step in Wnt signaling, probably explaining the strong effects of Ouabain on this pathway. In Xenopus embryos, brief Ouabain treatment at the 32-cell stage, critical for the earliest Wnt signal in development-inhibited brains, could be reversed by treatment with Lithium chloride, a Wnt mimic. Inhibiting membrane trafficking may provide a way of targeting Wnt-driven cancers.
Hormonal regulation of miRNA during mammary gland development
Authors: Confuorti Cameron , Jaramillo Maritza , Plante Isabelle 
Published: May 2024

ABSTRACT
The mammary gland is a unique organ as most of its development occurs after birth through stages of proliferation, differentiation and apoptosis that are tightly regulated by circulating hormones and growth factors. Throughout development, hormonal cues induce the regulation of different pathways, ultimately leading to differential transcription and expression of genes involved in this process, but also in the activation or inhibition of post-transcriptional mechanisms of regulation. However, the role of microRNAs (miRNAs) in the different phases of mammary gland remodeling is still poorly understood. The objectives of this study were to analyze the expression of miRNA in key stages of mammary gland development in mice and to determine whether it could be associated with hormonal variation between stages. To do so, miRNAs were isolated from mouse mammary glands at stages of adulthood, pregnancy, lactation and involution, and sequenced. Results showed that 490, 473, 419, and 460 miRNAs are detected in adult, pregnant, lactating and involuting mice, respectively, most of them being common to all four groups, and 58 unique to one stage. Most genes could be divided into six clusters of expression, including two encompassing the highest number of miRNA (clusters 1 and 3) and showing opposite profiles of expression, reaching a peak at adulthood and valley at lactation, or showing the lowest expression at adulthood and peaking at lactation. GO and KEGG analyses suggest that the miRNAs differentially expressed between stages influence the expression of targets associated with mammary gland homeostasis and hormone regulation. To further understand the links between miRNA expression and hormones involved in mammary gland development, miRNAs were then sequenced in breast cells exposed to estradiol, progesterone, prolactin and oxytocin. Four, 38, 24 and 66 miRNAs were associated with progesterone, estradiol, prolactin, and oxytocin exposure, respectively. Finally, when looking at miRNAs modulated by the hormones, differentially expressed during mammary gland development, and having a pattern of expression that could be correlated with the relative levels of hormones known to be found in vivo, 16 miRNAs were identified as likely regulated by circulating hormones. Overall, our study brings a better understanding of the regulation of miRNAs throughout mammary gland development and suggests that there is a relationship between their expression and the main hormones involved in mammary gland development. Future studies will examine this role more in detail.
The CD36 scavenger receptor Bez regulates lipid redistribution from fat body to ovaries in Drosophila
Authors: Carrera Pilar , Odenthal Johanna , Risse Katharina S. , Jung Yerin , Kuerschner Lars , Bülow Margret H. 
Published: May 2024

ABSTRACT
Lipid distribution in an organism is mediated by the interplay between lipoprotein particles, lipoprotein receptors and class B scavenger receptors of the CD36 family. CD36 is a multifunctional protein mediating lipid uptake, mobilization and signaling at the plasma membrane and inside of the cell. The CD36 protein family has 14 members in Drosophila melanogaster, which allows for the differentiated analysis of their functions. Here, we unravel a role for the so far uncharacterized scavenger receptor Bez in lipid export from Drosophila adipocytes. Bez shares the lipid binding residue with CD36 and is expressed at the plasma membrane of the embryonic, larval and adult fat body. Bez loss of function lowers the organismal availability of storage lipids and blocks the maturation of egg chambers in ovaries. We demonstrate that Bez interacts with the APOB homolog Lipophorin at the plasma membrane of adipocytes and trace the Bez-dependent transfer of an alkyne-labeled fatty acid from adipocytes to Lipophorin. Our study demonstrates how lipids are distributed by scavenger receptor–lipoprotein interplay and contribute to the metabolic control of development.
A short guide to the tight junction
Authors: Citi Sandra , Fromm Michael , Furuse Mikio , González-Mariscal Lorenza , Nusrat Asma , Tsukita Sachiko , Turner Jerrold R. 
Published: May 2024

ABSTRACT
Tight junctions (TJs) are specialized regions of contact between cells of epithelial and endothelial tissues that form selective semipermeable paracellular barriers that establish and maintain body compartments with different fluid compositions. As such, the formation of TJs represents a critical step in metazoan evolution, allowing the formation of multicompartmental organisms and true, barrier-forming epithelia and endothelia. In the six decades that have passed since the first observations of TJs by transmission electron microscopy, much progress has been made in understanding the structure, function, molecular composition and regulation of TJs. The goal of this Perspective is to highlight the key concepts that have emerged through this research and the future challenges that lie ahead for the field.
Oncologic Safety of Immediate Oncoplastic Surgery Compared with Standard Breast-Conserving Surgery for Patients with Invasive Lobular Carcinoma
Authors: Falade Israel , Switalla Kayla , Quirarte Astrid , Baxter Molly , Soroudi Daniel , Rothschild Harriet , Abe Shoko Emily , Goodwin Karen , Piper Merisa , Wong Jasmine , Foster Robert , Mukhtar Rita A. 
Published: May 2024

Abstract
Background
Invasive lobular carcinoma (ILC) of the breast grows in a diffuse pattern, resulting in a high risk of positive margins at surgical resection. Oncoplastic approaches have been shown to reduce this risk, but concerns persist around the safety of immediate oncoplastic surgery for those with ILC. This study evaluated the short- and long-term oncologic outcomes of immediate oncoplastic surgery for patients with ILC.

Methods
This study retrospectively analyzed an institutional database of stages I to III ILC patients who underwent breast-conserving surgery (BCS) with or without immediate oncoplastic surgery (oncoplastic closure or oncoplastic reduction mammoplasty [ORM]). The study compared positive margin rates, rates of successful BCS, and recurrence-free survival (RFS) by type of surgery.

Results
For 494 patients the findings showed that the use of immediate ORM was associated with significantly lower odds of positive margins (odds ratio [OR], 0.34; 95 % confidence interval [CI], 0.17–0.66; p = 0.002). Both lumpectomy with oncoplastic closure and ORM were significantly associated with higher rates of successful BCS than standard lumpectomy (94.2 %, 87.8 %, and 73.9 %, respectively; p < 0.001). No difference in RFS was observed between those undergoing immediate oncoplastic surgery and those undergoing standard lumpectomy alone.

Conclusions
The patients with stages I to III ILC who underwent immediate oncoplastic surgery had significant benefits including lower odds of positive margins and higher rates of successful BCS, with both types of immediate oncoplastic surgery showing similar RFS compared with lumpectomy alone. This supports the oncologic safety of immediate oncoplastic surgery for diffusely growing tumors such as ILC, providing it an ideal option for patients desiring BCS.
Location-Specificity and Relocation Incentive Programs for Remote Workers
Authors: Teodorovicz Thomaz , Choudhury Prithwiraj (Raj) , Starr Evan 
Published: May 2024

The precipitous growth of remote work has given rise to a new phenomenon: the emergence of relocation incentive programs that localities use to compete for the physical presence of remote workers. Remote workers with high general human capital may create value for their new destinations and reverse net talent outflow from smaller cities in middle America and globally. However, localities seeking to attract, retain, and create value from remote workers face significant challenges because such workers may have a low attachment to their new destination. Analogizing these challenges to the problem of creating and capturing value from workers with general human capital, we argue that localities can benefit from using relocation incentive program by leveraging location-specific attributes that create value for the individual and the locality. We examined these ideas in the context of Tulsa Remote, a program that provides relocation incentives and a bundle of services to increase engagement and embeddedness in Tulsa, Oklahoma. We found that Tulsa Remote increased community engagement, real income, and entrepreneurship of remote workers, benefiting both the community and the individual. Tulsa Remote increased the worker’s willingness to stay, and local community engagement is a key driver of this relationship. This work thus suggests that location specificity enables localities to both create and capture value from remote workers. Supplemental Material: The online appendix is available at https://doi.org/10.1287/orsc.2023.17712 .
3D visualization in turbid water using optimal photon counting and a GAT-based peplography method
Authors: Tehseen Riffat , Shahzad Muhammad , Mane Mithilesh K. , Ali Amjad , Zhang Zejun , Xu Jing 
Published: May 2024

Peplography is a three-dimensional (3D) approach for the visualization of targets in environments characterized by heavy scattering. It detects ballistic photons and subsequently generates a 3D image using integral imaging, where the expected number of ballistic photons is set arbitrarily. However, it affects the robustness of the method and accuracy in the analysis of results. Therefore, we propose a method to determine the optimal number of ballistic photons based on the maximum entropy of the photon counting image. Because accuracy in visualizing 3D targets may be compromised due to extraneous photons and fluctuations in photon intensity, we also address this challenge by integrating the generalized Anscombe transformation (GAT) with the conventional peplography technique. The noise caused by an image sensor during image acquisition can be modeled as a Poisson–Gaussian noise, and the photon counting process can be modeled as a Poisson process. Addressing such noise indirectly involves applying the GAT to the reconstructed image to stabilize its variance, denoising the stabilized data with a Gaussian denoising algorithm (i.e., non-local means filtering), and subsequently applying an exact unbiased inverse GAT to the denoised data. Experimental validation is conducted through experiments, with comparisons to conventional peplography, wavelet peplography, and a few standard dehazing and machine learning methods. Various image quality metrics such as correlation, structural similarity, the peak signal-to-noise ratio, and the natural image quality evaluator are used to demonstrate the superiority of the proposed method over conventional ones.
Fam96a is essential for the host control of Toxoplasma gondii infection by fine-tuning macrophage polarization via an iron-dependent mechanism
Authors: Liu Zhuanzhuan , Wang Hanying , Zhang Zhiwei , Ma Yulu , Jing Qiyue , Zhang Shenghai , Han Jinzhi , Chen Junru , Xiang Yaoyao , Kou Yanbo , Wei Yanxia , Wang Lu , Wang Yugang 
Published: May 2024

Background
Toxoplasmosis affects a quarter of the world’s population. Toxoplasma gondii (T.gondii) is an intracellular parasitic protozoa. Macrophages are necessary for proliferation and spread of T.gondii by regulating immunity and metabolism. Family with sequence similarity 96A (Fam96a; formally named Ciao2a) is an evolutionarily conserved protein that is highly expressed in macrophages, but whether it play a role in control of T. gondii infection is unknown.

Methodology/principal findings
In this study, we utilized myeloid cell-specific knockout mice to test its role in anti-T. gondii immunity. The results showed that myeloid cell-specific deletion of Fam96a led to exacerbate both acute and chronic toxoplasmosis after exposure to T. gondii. This was related to a defectively reprogrammed polarization in Fam96a-deficient macrophages inhibited the induction of immune effector molecules, including iNOS, by suppressing interferon/STAT1 signaling. Fam96a regulated macrophage polarization process was in part dependent on its ability to fine-tuning intracellular iron (Fe) homeostasis in response to inflammatory stimuli. In addition, Fam96a regulated the mitochondrial oxidative phosphorylation or related events that involved in control of T. gondii.

Conclusions/significance
All these findings suggest that Fam96a ablation in macrophages disrupts iron homeostasis and inhibits immune effector molecules, which may aggravate both acute and chronic toxoplasmosis. It highlights that Fam96a may autonomously act as a critical gatekeeper of T. gondii control in macrophages.
MVMRmode: Introducing an R package for plurality valid estimators for multivariable Mendelian randomisation
Authors: Woolf Benjamin , Gill Dipender , Grant Andrew J. , Burgess Stephen 
Published: May 2024

Background
Mendelian randomisation (MR) is the use of genetic variants as instrumental variables. Mode-based estimators (MBE) are one of the most popular types of estimators used in univariable-MR studies and is often used as a sensitivity analysis for pleiotropy. However, because there are no plurality valid regression estimators, modal estimators for multivariable-MR have been under-explored.

Methods
We use the residual framework for multivariable-MR to introduce two multivariable modal estimators: multivariable-MBE, which uses IVW to create residuals fed into a traditional plurality valid estimator, and an estimator which instead has the residuals fed into the contamination mixture method (CM), multivariable-CM. We then use Monte-Carlo simulations to explore the performance of these estimators when compared to existing ones and re-analyse the data used by Grant and Burgess (2021) looking at the causal effect of intelligence, education, and household income on Alzheimer’s disease as an applied example.

Results
In our simulation, we found that multivariable-MBE was generally too variable to be much use. Multivariable-CM produced more precise estimates on the other hand. Multivariable-CM performed better than MR-Egger in almost all settings, and Weighted Median under balanced pleiotropy. However, it underperformed Weighted Median when there was a moderate amount of directional pleiotropy. Our re-analysis supported the conclusion of Grant and Burgess (2021), that intelligence had a protective effect on Alzheimer’s disease, while education, and household income do not have a causal effect.

Conclusions
Here we introduced two, non-regression-based, plurality valid estimators for multivariable MR. Of these, “multivariable-CM” which uses IVW to create residuals fed into a contamination-mixture model, performed the best. This estimator uses a plurality of variants valid assumption, and appears to provide precise and unbiased estimates in the presence of balanced pleiotropy and small amounts of directional pleiotropy.
Patterns of cognitive-emotional change after cognitive-behavioural treatment in emotional disorders: A 12-month longitudinal cluster analysis
Authors: Barrio-Martínez Sara , Rodriguez-Perez Noelia , Priede Amador , Medrano Leonardo Adrián , Muñoz-Navarro Roger , Moriana Juan Antonio , Carpallo-González María , Prieto-Vila Maider , Ruiz-Rodríguez Paloma , Cano-Vindel Antonio , González-Blanch César 
Published: May 2024

Introduction
The aim of this study was to use cluster analysis based on the trajectory of five cognitive-emotional processes (worry, rumination, metacognition, cognitive reappraisal and expressive suppression) over time to explore differences in clinical and performance variables in primary care patients with emotional symptoms.

Methods
We compared the effect of adding transdiagnostic cognitive-behavioural therapy (TD-CBT) to treatment as usual (TAU) according to cluster membership and sought to determine the variables that predicted cluster membership. 732 participants completed scales about cognitive-emotional processes, anxiety and depressive symptoms, functioning, and quality of life (QoL) at baseline, posttreatment, and at 12 months. Longitudinal cluster analysis and logistic regression analyses were carried out.

Results
A two-cluster solution was chosen as the best fit, named as “less” or “more” improvement in cognitive-emotional processes. Individuals who achieved more improvement in cognitive-emotional processes showed lower emotional symptoms and better QoL and functioning at all three time points. TAU+TD-CBT, income level, QoL and anxiety symptoms were significant predictors of cluster membership.

Conclusions
These results underscore the value of adding TD-CBT to reduce maladaptive cognitive-emotional regulation strategies. These findings highlight the importance of the processes of change in therapy and demonstrate the relevance of the patient’s cognitive-emotional profile in improving treatment outcomes.