bluuebunny/crossref_metadata_2025 huggingface dataset:
PD-L1 Expression and Silva Invasion Pattern in Villoglandular Adenocarcinoma of the Uterine Cervix
Authors: Dietl Anna K. , Beckmann Matthias W. , Stuebs Frederik A. , Gass Paul , Emons Julius , Hartmann Arndt , Erber Ramona
Published: January 2024

Villoglandular adenocarcinoma (VGA) of the uterine cervix is a rare subtype of endocervical adenocarcinoma in young women. Between 2007 and 2020, all women with endocervical adenocarcinoma were retrospectively reviewed to find patients with VGA. Eight patients in whom pure VGA had been diagnosed were included. The mean age at initial diagnosis was 36.3 years (range 24–46). After surgical treatment, patients were followed up for 59 months (range 16–150). To date, all patients are alive with no evidence of disease. Neither lymph node involvement nor lymphovascular invasion was found. Furthermore, we examined the samples with a focus on morphological invasion pattern (Silva), stromal tumor-infiltrating lymphocytes (sTILs), and immunohistochemical programmed death ligand-1 (PD-L1) expression. PD-L1 expression was observed in 7/8 using the combined positive score (cutoff≥1%), 1/8 of VGAs using the tumor proportion score (cutoff≥1%), and 7/8 using the immune cell (cutoff≥1%). Using combined positive score and immune cell, PD-L1 expression was seen in 7/8 of pattern B and C tumors, with significantly higher expression in tumors with destructive-type patterns (P<0.05, A vs. B+C). Using tumor proportion score, no significant difference in PD-L1 expression was seen between VGAs with different invasion patterns. VGAs demonstrated twice higher sTILs in tumors with destructive-type invasion patterns. Our observations suggest that PD-L1 expression, tumor invasion patterns, and sTILs do not correlate with the excellent prognosis of pure VGA.
Foreign Language Learning
Authors: Angulo-Jiménez Henry , Bonilla-López Marisela , Rojas-Ramírez Esteban
Published: January 2024

Purpose:

Although autistic perspectives are paramount for evidence-based practice and the neurodiversity paradigm, they are often underrepresented in research and have only recently started to get attention from professionals in different fields, including communication sciences and disorders (CSD) and foreign language teaching (FLT). To alleviate this situation, we conducted an exploratory study on the experiences of self-identified autistic bloggers with foreign language learning (FLL).

Methods:

We used deductive thematic analysis to characterize the bloggers and establish the perceived effect of autism on FLL.

Results:

Our analysis of 14 blog posts revealed that the typical blogger had an autism diagnosis, spoke English natively, and had learned Spanish or French as a foreign language through formal instruction and/or self-teaching. We also found that all the bloggers acknowledged both positive and negative effects of autism on FLL, with more bloggers focusing on positive effects.

Conclusions:

Findings highlight the need for professionals in CSD and FLT to (a) avoid making assumptions about the FLL capabilities of autistic individuals, (b) consult with autistic individuals regarding the perceived value of autistic traits for FLL, and (c) engage in interprofessional practice with each other.
Revealing Conflicting Ideologies
Authors: Vidal Verónica , Urra Pamela , Cerda Diez María Fernanda , Becerra León Carla , Ramos Alarcón María Consuelo , Cortés Juan P.
Published: January 2024

The discussion about the words and concepts related to autism is alive in the scholarly community, tacitly or explicitly. Contrasting ideologies linked to the medical model and neurodiversity paradigm underlie terminology referring to autism. The present proof-of-concept study conducted a critical discourse analysis of the terminology (i.e., microstructure) used to describe autism in two academic journals across four decades. Specifically, we utilized the framework provided by Bottema-Beutel et al. (2021) to analyze 35 articles published in Journal of Autism and Developmental Disorders and Autism. These articles were reviewed with a focus on terminology used to describe the concept of autism, autistic individuals, and nonautistic individuals. The main findings support the feasibility of this proof-of-concept study. They revealed a predominant use of potentially ableist language across the four decades and a slow incorporation of alternative terms usually linked with more inclusive language in the last decade. We suggest that this change has been driven by the autistic community in a process of democratizing the role of experts. Accordingly, we recommend including autistic individuals' choices to designate their community.
COVID-19 Reinfection Has Better Outcomes Than the First Infection in Solid Organ Transplant Recipients
Authors: Solera Javier T. , Árbol Berta G. , Mittal Ankit , Hall Victoria G. , Marinelli Tina , Bahinskaya Ilona , Humar Atul , Kumar Deepali
Published: January 2024

Background.

Solid organ transplant recipients face an increased risk of severe coronavirus disease 2019 (COVID-19) and are vulnerable to repeat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. In nonimmunocompromised individuals, SARS-CoV-2 reinfections are milder likely because of cross-protective immunity. We sought to determine whether SARS-CoV-2 reinfection exhibits milder manifestations than primary infection in transplant recipients.

Methods.

Using a large, prospective cohort of adult transplant patients with COVID-19, we identified patients with SARS-CoV-2 reinfections. We performed a 1:1 nearest neighbor propensity score matching to control potential confounders, including the COVID-19 variant. We compared outcomes including oxygen requirement, hospitalization, and intensive care unit admission within 30 d after diagnosis between patients with reinfection and those with the first episode of COVID-19.

Results.

Between 2020 and 2023, 103 reinfections were identified in a cohort of 1869 transplant recipients infected with SARS-CoV-2 (incidence of 2.7% per year). These included 50 kidney (48.5%), 27 lung (26.2%), 7 heart (6.8%), 6 liver (5.8%), and 13 multiorgan (12.6%) transplants. The median age was 54.5 y (interquartile range [IQR], 40.5–65.5) and the median time from transplant to first infection was 6.6 y (IQR, 2.8–11.2). The time between the primary COVID-19 and reinfection was 326 d (IQR, 226–434). Three doses or more of SARS-CoV-2 vaccine are received by 87.4% of patients. After propensity score matching, reinfections were associated with significantly lower hospitalization (5.8% versus 19.4%; risk ratio, 0.3; 95% CI, 0.12-0.71) and oxygen requirement (3.9% versus 13.6%; risk ratio, 0.29; 95% CI, 0.10-0.84). In a within-patient analysis only in the reinfection group, the second infection was milder than the first (3.9% required oxygen versus 19.4%, P < 0.0001), and severe first COVID-19 was the only predictor of severe reinfection.

Conclusions.

Transplant recipients with COVID-19 reinfection present better outcomes than those with the first infection, providing clinical evidence for the development of cross-protective immunity.
Optic Neuropathy Associated with POLG Mutations: A Case Series and Literature Review
Authors: Reitinger Jeremy C. , Mackay Devin D.
Published: January 2024

Background:

The clinical characteristics of patients with polymerase gamma (POLG) mutation-associated optic neuropathy remain incompletely characterized.

Methods:

We describe the clinical characteristics of 3 patients with POLG-associated optic neuropathy. We performed a literature review of optic neuropathy cases associated with POLG mutations and compared them with our cohort.

Results:

Many published cases of POLG-associated optic neuropathy in our literature review lacked details regarding severity of vision loss, visual field defects, and optical coherence tomography analysis. The clinical presentation of POLG mutations remains widely variable in age (from pediatric cases to adults) and associated systemic findings. All patients in our literature review presented with systemic symptoms, most commonly muscle weakness, ptosis, and ophthalmoplegia, whereas many young patients had severe systemic symptoms. In our case series, all 3 cases had isolated optic neuropathy affecting the papillomacular bundle, with signs such as reduced visual acuity and color vision, central visual field defects, temporal retinal nerve fiber layer loss with temporal optic disc pallor, and retinal ganglion cell complex loss. In addition, 2 of the 3 cases had added mitochondrial stressors in addition to the POLG mutation.

Conclusions:

Clinicians should be aware that POLG mutations can present as isolated optic neuropathy primarily affecting the papillomacular bundle. With mitochondrial failure being the likely underlying pathogenic mechanism in POLG-associated optic neuropathy, helping affected patients eliminate mitochondrial stressors may be important in reducing the risk for progressive vision loss in this otherwise currently untreatable disorder.
Urban tolerance does not protect against population decline in North American birds
Authors: Petrenko Julianna A. , Martin Paul R. , Fanelli Rachel E. , Bonier Frances
Published: January 2024

Population declines of organisms are widespread and severe, but some species' populations have remained stable, or even increased. The reasons some species are less vulnerable to population decline than others are not well understood. Species that tolerate urban environments often have a broader environmental tolerance, which, along with their ability to tolerate one of the most human-modified habitats (i.e. cities), might allow them to persist in the face of diverse anthropogenic challenges. Here, we examined the relationship between urban tolerance and annual population trajectories for 397 North American bird species. Surprisingly, we found that urban tolerance was unrelated to species’ population trajectories. The lack of a relationship between urban tolerance and population trajectories may reflect other factors driving population declines independent of urban tolerance, challenges that are amplified in cities (e.g. climate warming, disease), and other human impacts (e.g. conservation efforts, broad-scale land-use changes) that have benefitted some urban-avoidant species. Overall, our results illustrate that urban tolerance does not protect species against population decline.
Henry Elderfield. 25 April 1943—19 April 2016
Authors: McCave Ian Nicholas , Hodell David Arnold
Published: January 2024

Henry (always known as Harry) Elderfield was a marine geochemist whose pioneering measurements of strontium and its isotopes, rare earth elements and manganese in seawater and sediment pore waters gave him insights into the circulation of fluids into, through and out of the oceanic crust and marine sediments and their control of the chemical composition of the oceans. He provided the basis for proxies of past ocean temperatures, pH and water mass distributions. These he used to reveal changes in global temperature and sea-levels on timescales spanning the last 50 million years (Myr) with emphasis on the last 1 Myr of glacial/interglacial history. His work on a proxy for pH, coupled with understanding of the dissolved carbon system in seawater, allowed examination of problems of ocean acidification caused by past changes of atmospheric CO
2
. His manner of gentle persuasion underpinned by rigorous chemistry was passed on to more than 40 research students, and his proxy methods are in daily use by hundreds worldwide.
Viscoelastic materials are most energy efficient when loaded and unloaded at equal rates
Authors: Tsai Lucien , Navarro Paco , Wu Siqi , Levinson Taylor , Mendoza Elizabeth , Janneke Schwaner M. , Daley Monica A. , Azizi Emanuel , Ilton Mark
Published: January 2024

Biological springs can be used in nature for energy conservation and ultra-fast motion. The loading and unloading rates of elastic materials can play an important role in determining how the properties of these springs affect movements. We investigate the mechanical energy efficiency of biological springs (American bullfrog plantaris tendons and guinea fowl lateral gastrocnemius tendons) and synthetic elastomers. We measure these materials under symmetric rates (equal loading and unloading durations) and asymmetric rates (unequal loading and unloading durations) using novel dynamic mechanical analysis measurements. We find that mechanical efficiency is highest at symmetric rates and significantly decreases with a larger degree of asymmetry. A generalized one-dimensional Maxwell model with no fitting parameters captures the experimental results based on the independently characterized linear viscoelastic properties of the materials. The model further shows that a broader viscoelastic relaxation spectrum enhances the effect of rate-asymmetry on efficiency. Overall, our study provides valuable insights into the interplay between material properties and unloading dynamics in both biological and synthetic elastic systems.
Enhanced photoelectrochemical performance of quantum dot-sensitized solar cell using Cu
2+
co-doped CdS and CdSe nanoscrystals
Authors: Tuan Thi Tran Anh , Tung Ha Thanh , Chinh Truong Thi Ngoc , Hung Phan Thanh , Dang Huu Phuc
Published: January 2024

Today, nanoscrystals are researched and developed very quickly because of their advantages in many areas of life. One of the potential applications is quantum dot-sensitized solar cells. This is a green, clean, environmentally friendly cell, and has been studied by scientists since 2000. In this study, we fabricated photoanodes with Cu
2+
ions co-doped into cadmium sulfide (CdS) and cadmium selenide (CdSe) nanoscrystals by successive ionic layer adsorption and reaction, and chemical bath deposition methods to improve absorption spectral intensity of films. The results showed that the absorption intensity increased by eight times compared with our previous results on Cu
2+
ions doped with CdSe nanoscrystals. The CdS:Cu
2+
film is optimized at 2% doping, the efficiency is 4.6819%, and the current density is 27.3501 mA.cm
−2
, which is higher when compared with the Cu
2+
ion only doped into the CdSe quantum dot (19.915 mA.cm
−2
). In addition, the composition of the photoanode was determined by surface and cross-sectional field-emission scanning electron microscope images, and the structure of the film was determined by X-ray diffraction, energy-dispersive X-ray spectroscopy mapping and X-ray photoelectron spectroscopy. Finally, the film's optical properties were studied by ultraviolet-visible spectroscopy, photoluminescence spectroscopy and electrochemical properties by electrochemical impedance spectroscopy. The results obtained have been discussed and presented in great detail.
Aged Tendons Exhibit Altered Mechanisms of Strain-Dependent Extracellular Matrix Remodeling
Authors: Aggouras Anthony N. , Stowe Emma J. , Mlawer Samuel J. , Connizzo Brianne K.
Published: January 2024

Aging is a primary risk factor for degenerative tendon injuries, yet the etiology and progression of this degeneration is poorly understood. While aged tendons have innate cellular differences that support a reduced ability to maintain mechanical tissue homeostasis, the response of aged tendons to altered levels of mechanical loading has not yet been studied. To address this question, we subjected young and aged murine flexor tendon explants to various levels ofin vitrotensile strain. We first compared the effect of static and cyclic strain on matrix remodeling in young tendons, finding that cyclic strain is optimal for studying remodelingin vitro. We then investigated the remodeling response of young and aged tendon explants after 7 days of varied mechanical stimulus (stress-deprivation, 1%, 3%, 5%, or 7% cyclic strain) via assessment of tissue composition, biosynthetic capacity, and degradation profiles. We hypothesized that aged tendons would show muted adaptive responses to changes in tensile strain and exhibit a shifted mechanical setpoint, at which the remodeling balance is optimal. Interestingly, we found 1% cyclic strain best maintains native physiology while promoting ECM turnover for both age groups. However, aged tendons display fewer strain-dependent changes, suggesting a reduced ability to adapt to altered levels of mechanical loading. This work has significant impact in understanding the regulation of tissue homeostasis in aged tendons, which can inform clinical rehabilitation strategies for treating elderly patients.
Archaeological Ivories: A practical guide for identifying elephant and hippo ivory in the archaeological record
Authors: Shochat Harel
Published: January 2024

The use of osseous materials for crafting various artifacts is well-attested in the archaeological record of the ancient Near East. While bone, the most common and available material, was used more frequently, ivory was highly valued as an exotic material for fashioning exquisite prestige items designed for ostentatious display and linked to society’s elite strata. Therefore, reliably distinguishing between the taxonomic origins of the osseous artifacts is significant for interpreting the archaeological data. In the Near East, the demand for ivory products reached its zenith during the mid-2ndto mid-1stmillennia BCE, producing one of the largest assemblages unearthed anywhere in the world. Using state-of-the-art bio-molecular analyses to study this collection is costly, time-consuming, and entails damaging the highly-curated artifacts. This paper provides an essential, simple, non-destructive, and validated method to distinguish bone from elephant or hippo ivory (the most common osseous materials attested in the Near East record). However, following similar guidelines can help index other biological sources of ivory.
The Flash Mode of Proton Irradiation in the Bragg Peak Partly Spares the Embryogenesis of the Quail
Authors: Akulinichev Sergey V. , Glukhov Segrey I. , Gavrilov Yury K. , Kokontsev Dmitry A. , Kuznetsova Elena A. , Martynova Valeriia V. , Yakovlev Ivan A.
Published: January 2024

The study of biological effects of high-dose-rate ionizing radiation using animal models remains an urgent problem. In the work, a comparison of proton-induced damage to embryos (the 9thpost-fertilization day) and 1-day-old baby chicks (the 18thpost-fertilization day) from irradiated eggs of Japanese quail (Coturnix coturnix japónica) irradiated in and outside the Bragg peak with the conventional and ultra-high dose rate D (CONV D < 1 Gy/s, FLASH D ∼100 Gy/s and single-pulse flash - SPLASH D ∼106Gy/s, respectively) was carried out. The following criteria were used: survival, body weight and body length of embryos, weight of chicks, percentage of erythrocytes with anomalies (with micronuclei, without nuclei, with two nuclei), and the speed of movement of 1-day-old chicks in the open field test. The largest number of dead embryos was recorded after irradiation with 7 and 14 Gy in the plateau region of the proton trajectory. By the criteria of body weight and length, as well as the number of erythrocytes with micronuclei in 9-day-old embryos from eggs irradiated with a dose of 8.5 Gy in the Bragg peak, FLASH and SPLASH modes were found to be the least traumatic compared with the CONV mode. The weight of chicks from eggs irradiated with a dose of 4 Gy in the Bragg peak did not differ from the control and did not depend on the irradiation mode. The lowest death incidence and the smallest number of abnormal erythrocytes were recorded after FLASH and SPLASH irradiation; in chicks that hatched from eggs irradiated in the CONV mode, a tendency for an increase in the number of abnormal erythrocytes was observed. The speed of movement of chicks from FLASH- and SPLASH-irradiated eggs was comparable with that from unirradiated eggs, and chicks from eggs irradiated in the CONV mode were less active than chicks from unirradiated eggs and eggs irradiated in the other regimes. Thus, the irradiation of eggs with a beam of accelerated protons in the Bragg peak in the FLASH/SPLASH modes is less damaging for healthy tissues and for the development of embryos and chicks on the cellular, anatomical, and physiological levels.
Transdifferentiation of epithelial cells and fibroblasts induced by IL-1β fuels neutrophil recruitment in chronic rhinosinusitis
Authors: Xie Xinyu , Wang Pin , Jin Min , Wang Yue , Qi Lijie , Wu Changhua , Guo Shu , Li Changqing , Zhang Xiaojun , Yuan Ye , Ma Xinyi , Liu Fangying , Liu Weiyuan , Liu Heng , Duan Chen , Ye Ping , Li Xuezhong , Borish Larry , Zhao Wei , Feng Xin
Published: January 2024

Neutrophilic inflammation contributes to multiple chronic inflammatory airway diseases, including asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), and is associated with an unfavorable prognosis. Here, using single-cell RNA sequencing (scRNA-seq) to profile human nasal mucosa obtained from the inferior turbinates, middle turbinates, and nasal polyps of CRSwNP patients, we identified two IL-1 signaling-induced cell subsets—LY6D+club cells andIDO1+fibroblasts—that promote neutrophil recruitment by respectively releasing S100A8/A9 and CXCL1/2/3/5/6/8 into inflammatory regions. IL-1β, a pro-inflammatory cytokine involved in IL-1 signaling, induces the transdifferentiation ofLY6D+club cells andIDO1+fibroblasts from primary epithelial cells and fibroblasts, respectively. In an LPS-induced neutrophilic CRSwNP mouse model, blocking IL-1β activity with a receptor antagonist significantly reduced the numbers ofLY6D+club cells andIDO1+fibroblasts and mitigated nasal inflammation. This study reveals the roles of two cell subsets in neutrophil recruitment and demonstrates an IL-1-based intervention for mitigating neutrophilic inflammation in CRSwNP.
β-Catenin associates with a Wnt signaling mRNA network in myeloid cells through canonical RBP binding
Authors: Wagstaff M , Sevim O , Goff A , Raynor M , Park H , Mancini E , Nguyen DTT , Chevassut T , Blair A , Castellano L , Newbury S , Towler B , Morgan RG
Published: January 2024

Wnt/β-catenin signaling is important for normal hematopoietic stem/progenitor cell (HSPC) biology and heavily implicated in acute myeloid leukaemia (AML). The central mediator β-catenin is an attractive therapeutic target in AML however its targeting has been hampered by poor characterisation of its molecular interactions in haematopoietic cells. Our previous β-catenin interactome study identified the significant enrichment of RNA-binding proteins (RBP) implying post-transcriptional roles for β-catenin in myeloid cells. To identify β-catenin-associated mRNAs we performed β-catenin RNA-immunoprecipitation coupled to RNA-sequencing (RIP-seq) and identified significantly enriched Wnt signalling pathway transcripts. Using β-catenin cross-linking immunoprecipitation (CLIP) we demonstrated a limited capacity for β-catenin to bind RNA directly implying dependence on other RBPs. β-Catenin was found to interact with MSI2 in both myeloid cell lines and AML patient samples, where expression was significantly correlated. MSI2 knockdown reduced Wnt signalling output (TCF/LEF activity), through suppression of LEF-1 expression and nuclear localization. Through both RIP and CLIP we demonstrate MSI2 bindsLEF1mRNA in a partly β-catenin dependent fashion, and may impact the post-transcriptional control of LEF-1 expression. Finally, we show that MSI2-mediated expansion of human HSPCs could be partly driven throughLEF1regulation. This is the first study to show functional crosstalk between MSI2 and Wnt signalling in human cells, and indicates potential novel post-transcriptional roles for β-catenin in a haematological context.
An integrated signaling threshold initiates IgG response towards virus-like immunogens
Authors: Wholey Wei-Yun , Meyer Alexander R. , Yoda Sekou-Tidiane , Mueller James L. , Mathenge Raisa , Chackerian Bryce , Zikherman Julie , Cheng Wei
Published: January 2024

Class-switched neutralizing antibody (nAb) production is rapidly induced upon many viral infections. However, due to the presence of multiple components in typical virions, the precise biochemical and biophysical signals from viral infections that initiate nAb responses remain inadequately defined. Using a reductionist system of synthetic virus-like structures (SVLS) containing minimal, highly purified biochemical components commonly found in enveloped viruses, here we show that a foreign protein on a virion-sized liposome can serve as a stand-alone danger signal to initiate class-switched nAb responses in the absence of cognate T cell help or Toll-like receptor signaling but requires CD19, the antigen (Ag) coreceptor on B cells. Introduction of internal nucleic acids (iNAs) obviates the need for CD19, lowers the epitope density (ED) required to elicit the Ab response and transforms these structures into highly potent immunogens that rival conventional virus-like particles in their ability to elicit strong Ag-specific IgG. As early as day 5 after immunization, structures harbouring iNAs and decorated with just a few molecules of surface Ag at doses as low as 100 ng induced all IgG subclasses of Ab known in mice and reproduced the IgG2a/2c restriction that has been long observed in live viral infections. These findings reveal a shared mechanism for nAb response upon viral infection. High ED is capable but not necessary for driving Ab secretionin vivo. Instead, even a few molecules of surface Ag, when combined with nucleic acids within these structures, can trigger strong antiviral IgG production. As a result, the signaling threshold for the induction of neutralizing IgG is set by dual signals originating from both ED on the surface and the presence of iNAs within viral particulate immunogens.

One-sentence summary

Reconstitution of minimal viral signals necessary to initiate antiviral IgG
A systematic evaluation of computational methods for cell segmentation
Authors: Wang Yuxing , Zhao Junhan , Xu Hongye , Han Cheng , Tao Zhiqiang , Zhou Dawei , Geng Tong , Liu Dongfang , Ji Zhicheng
Published: January 2024

Cell segmentation is a fundamental task in analyzing biomedical images. Many computational methods have been developed for cell segmentation and instance segmentation, but their performances are not well understood in various scenarios. We systematically evaluated the performance of 18 segmentation methods to perform cell nuclei and whole cell segmentation using light microscopy and fluorescence staining images. We found that general-purpose methods incorporating the attention mechanism exhibit the best overall performance. We identified various factors influencing segmentation performances, including image channels, choice of training data, and cell morphology, and evaluated the generalizability of methods across image modalities. We also provide guidelines for choosing the optimal segmentation methods in various real application scenarios. We developed Seggal, an online resource for downloading segmentation models already pre-trained with various tissue and cell types, substantially reducing the time and effort for training cell segmentation models.
DysregulatedSASS6expression promotes increased ciliogenesis and cell invasion phenotypes
Authors: Hargreaves Eleanor , Jenks Andrew D , Staszewski Adina , Tsalikis Athanasios , Bodoque Raquel , Arias-Garcia Mar , Abdi Yasmin , Al-Malki Abdulaziz , Yuan Yinyin , Natrajan Rachael , Haider Syed , Iskratsch Thomas , Wang Won-Jing , Godinho Susana , Palaskas Nicolaos J , Calvo Fernando , Zech Tobias , Tanos Barbara
Published: January 2024

Centriole and/or cilia defects are characteristic of cancer cells and have been linked to cancer cell invasion. However, the mechanistic basis of these effects is unknown. Spindle assembly abnormal protein 6 homolog (SAS-6) is essential for centriole biogenesis and cilia formation. In cycling cells, SAS-6 undergoes APCCdh1-mediated targeted degradation by the 26S proteasome at the end of mitosis. Little is known about the function of SAS-6 outside of centrosome biogenesis. To examine this, we expressed a non-degradable SAS-6 mutant (SAS-6ND). Expression of SAS-6ND led to an increase in ciliation and cilia-dependent cell invasion, and caused an upregulation of the YAP/TAZ pathway. YAP/TAZ or ciliogenesis inhibition prevented SAS-6-induced invasion. SAS-6ND caused increased actin alignment and stress fiber coherency, and nuclear flattening known to promote YAP nuclear import. Finally, data from The Cancer Genome Atlas showed that SAS-6 overexpression is associated with poor prognosis in various cancers. Our data provide evidence for a defined role of SAS-6 in cancer cell invasion and offers mechanistic insight into the role of YAP/TAZ in this cilia-sensitive process.

Synopsis

SAS-6 overexpressing cells show increased ciliation, actin cytoskeleton reorganization, cell flattening, YAP pathway activation and increased invasion
BioXNet: a biologically inspired neural network for deciphering anti-cancer drug response in precision medicine
Authors: Yang Jiannan , Kei Wu William Ka , Man Hui Rina Yee , Kei Wong Ian Chi , Zhang Qingpeng
Published: January 2024

Accurate prediction of anti-cancer drug responses in preclinical and clinical studies is crucial for drug discovery and personalized medicine. While machine learning models have demonstrated promising prediction accuracy in this task, their translational value in cancer therapy is constrained by the lack of model interpretability and insufficient patients’ data with genomic profiles to calibrate models. The rich cell line data has the potential to supplement patients’ data, but the difference between the drug response mechanisms in cell lines and human body needs to be characterized quantitatively. To address these challenges, we proposed the BioXNet, which captures drug response mechanisms by seamlessly integrating drug target information with genomic profiles (genetic and epigenetic modifications) into a single biologically inspired neural network. BioXNet exhibited superior performance in drug response prediction tasks in both preclinical and clinical settings. An analysis of BioXNet’s interpretability revealed its ability to identify significant differences in drug response mechanisms between cell lines and the human body. Notably, the key factor of drug response is the drug targeting genes in cell lines but methylation modifications in the human body. Furthermore, we developed an online human-readable interface of BioXNet for drug response exploration by medical professionals and laymen. BioXNet represents a step further towards unifying drug, cell line and patients’ data under a holistic interpretable machine learning framework for precision medicine in cancer therapy.
Diving into broad-scale and high-resolution population genomics to decipher drivers of structure and climatic vulnerability in a marine invertebrate
Authors: Bourret Audrey , Leung Christelle , Puncher Gregory N. , Corre Nicolas Le , Deslauriers David , Skanes Katherine , Bourdages Hugo , Ros Manon Cassista-Da , Walkusz Wojciech , Jeffery Nicholas W. , Stanley Ryan R. E. , Parent Geneviève J.
Published: January 2024

Species with widespread distributions play a crucial role in our understanding of climate change impacts on population structure. In marine species, population structure is often governed by both high connectivity potential and selection across strong environmental gradients. Despite the complexity of factors influencing marine populations, studying species with broad distribution can provide valuable insights into the relative importance of these factors and the consequences of climate-induced alterations across environmental gradients. We used the northern shrimpPandalus borealisand its wide latitudinal distribution to identify current drivers of population structure and predict the species vulnerability to climate change. Individuals sampled across 24° latitude were genotyped at high geographic-(54 stations) and genetic-(14,331 SNPs) resolutions to assess genetic variation and environmental correlations. Four populations were identified in addition to finer substructure associated to local adaptation. Geographic patterns of neutral population structure reflected predominant oceanographic currents, while a significant proportion of the genetic variation was associated with gradients in salinity and temperature. Adaptive landscapes generated using climate projections suggest a larger genomic offset in the southern extent of theP. borealisrange, where shrimp had the largest adaptive standing genetic variation. Our genomic results combined with recent observations point to the non-recovery in southern regions and an impending vulnerable status in the regions at higher latitude forP. borealis. They also provide rare insights into the drivers of population structure and climatic vulnerability of a widespread meroplanktonic species, which is crucial to understand future challenges associated with invertebrates essential to ecosystem functioning.
Chloride binding to prestin does not influence very high-frequency complex nonlinear capacitance (cNLC) in the mouse outer hair cell
Authors: Bai Jun-Ping , Zhang Chenou , Bahader Iman , Strenzke Nicola , Renigunta Vijay , Oliver Dominik , Navaratnam Dhasakumar , Beckstein Oliver , Santos-Sacchi Joseph
Published: January 2024

Prestin (SLC26a5) function evolved to enhance auditory sensitivity and frequency selectivity by providing mechanical feedback via outer hair cells (OHC) into the organ of Corti. Its effectiveness is governed by the voltage-dependent kinetics of the protein’s charge movements, namely, nonlinear capacitance (NLC). We study the frequency response of NLC in the mouse OHC, a species with ultrasonic hearing. We find that the characteristic frequency cut-off (Fis) for the mouse in near 27 kHz. Single point mutations within the chloride binding pocket of prestin (e.g., S396E, S398E) lack the protein’s usual anion susceptibility. In agreement, we now show absence of anion binding in these mutants through molecular dynamics (MD) simulations. NLC Fisin the S396E knock-in mouse is unaltered, indicating that high frequency activity is not governed by chloride, but more likely by viscoelastic loads within the membrane. We also show that the allosteric action of chloride does not underlie piezoelectric-like behavior in prestin, since tension sensitivity of S396E NLC is comparable to that of WT. Because prestin structures of all species studied to-date are essentially indistinguishable, with analogous chloride binding pockets, auditory requirements of individual species for cochlear amplification likely evolved to enhance prestin performance by modifying, not its protein-anion interaction, but instead external mechanical loads on the protein.

Significance

Prestin is believed to provide cochlear amplification in mammals that possess a wide range of frequency sensitivities. Previously, chloride anions have been shown to control prestin kinetics at frequencies below 10 kHz. However, now we find that chloride binding is not influential for prestin kinetics in the very high range of the mouse. We suggest that such high frequency prestin performance is governed by impinging mechanical loads within the membrane, and not interactions with anions.
Repairing a deleterious domestication variant in a floral regulator gene of tomato by base editing
Authors: Glaus Anna N. , Brechet Marion , Swinnen Gwen , Lebeigle Ludivine , Iwaszkiewicz Justyna , Ambrosini Giovanna , Julca Irene , Zhang Jing , Roberts Robyn , Iseli Christian , Guex Nicolas , Jiménez-Gómez José , Glover Natasha , Martin Gregory B. , Strickler Susan , Soyk Sebastian
Published: January 2024

Crop genomes accumulated deleterious mutations, a symptom known as the cost of domestication. Precision genome editing has been proposed to eliminate such potentially harmful mutations, however, experimental demonstration is lacking. Here, we identified a deleterious mutation in the tomato transcription factorSUPPRESSOR OF SP2(SSP2), which became prevalent in the domesticated germplasm and diminished DNA-binding to genome-wide targets. We found thatSSP2acts partially redundant with its paralogSSPto regulate shoot and inflorescence architecture. However, redundancy was compromised during tomato domestication and completely lost in the closely-related speciesPhysalis grisea, in which a single ortholog regulates shoot branching. We applied base editing to directly repair the deleterious mutation in cultivated tomato and obtained plants with compact growth that provide an early fruit yield. Our work shows how deleterious variants sensitized modern genotypes for phenotypic tuning and illustrates how repairing deleterious mutations with genome editing may allow predictable crop improvement.
Systematic investigation of interindividual variation of DNA methylation in human whole blood
Authors: Grant Olivia A. , Kumari Meena , Schalkwyk Leonard , Zabet Nicolae Radu
Published: January 2024

Interindividual genetic variability is well characterised, but we still lack a complete catalogue of loci displaying variable and stable epigenetic patterns. Here, we report a catalogue of stable and variable interindividual DNA methylation in human whole blood by analysing the DNA methylation patterns in 3642 individuals using the IlluminaEPIC array. Our results showed that 41,216 CpGs display stable methylation (SMPs) and 34,972 CpGs display variable methylation levels (VMPs). This catalogue will be a useful resource for interpretation of results when associating epigenetic signals to phenotypes. We observed that SMPs are highly enriched in CpG islands, depleted at CpG shelves and open sea regions of the genome. In addition, we found that the VMPs were under higher genetic control than the SMPs and that trans mQTL pairs are often located in the same TAD or connected by chromatin loops. A subset of these VMPs (784) were classified as putative epialleles and our results demonstrate that these loci located in regulatory regions exhibit a link with gene expression.
Lead in the head: persistent lead poisoning of waterfowl in the Camargue (southern France) ten years after the ban on the use of lead shot in wetlands
Authors: Béchet Arnaud , Olivier Anthony , Cavallo François , Sauvajon Lou , Champagnon Jocelyn , Defos du Rau Pierre , Mondain-Monval Jean-Yves
Published: January 2024

Lead pollution remains a worldwide environmental and health issue with persistent detrimental effects on human and wildlife. Despite having been identified as an issue for wildlife a long time ago, the use of lead shot for hunting in wetlands was banned only in 2006 in France. Here, we took advantage of a long-term monitoring of waterfowl lead shot contamination in the Camargue (southern France) to (1) assess the local effectiveness of the French regulation in reducing waterfowl contamination and to (2) assess local compliance regarding the use of nontoxic shots in wetlands from 2007 onwards. We collected waterfowl gizzard from 38 hunters in the Camargue during 20 hunting seasons (1998 to 2017) for a total of 2306 gizzards from 28 different species. From 2008 to 2019, we also systematically collected the cartridge casings at three sites of communal wetland hunting. Ratio of lead vs nontoxic cartridges found in the field allowed monitoring hunter compliance with the new regulation. Despite a ten-year long ban on lead shot our results do not show any significant reduction in waterfowl exposure to lead through shot ingestion in the Camargue over the 20-year monitoring period. Indeed, gizzards of harvested waterfowl were as likely to contain at least one lead shot before the ban as after with a mean prevalence of 12% over the 13 species considered across the study period. Cartridge casings showed the persistence of use of lead shots by hunters in the Camargue wetlands despite a slow increase in the use of nontoxic cartridges. This unequivocally indicates that the law is far from being strictly applied, pointing to an insufficient policy enforcement. Our results support the need for a complete ban of lead ammunition for both wetland and terrestrial wildfowl which will facilitate policy enforcement and compliance.
Immunomodulatory Porous Regenerative Scaffolds forin situVascular Engineering
Authors: Zhen Le , Quiroga Elina , Creason Sharon A. , Chen Ningjing , Sapre Tanmay R. , Snyder Jessica M. , Lindhartsen Sarah L. , Fountaine Brendy S. , Barbour Michael C. , Faisal Syed , Aliseda Alberto , Johnson Brian W. , Himmelfarb Jonathan , Ratner Buddy D.
Published: January 2024

The 70-year quest for synthetic vascular graft (sVG) endothelialization has not led to completely healed endothelium in clinically used sVGs. In humans, healing is limited to the vicinity of anastomotic regions (pannus ingrowth) and does not reach the middle regions of sVGs. Here, we conducted proof-of-concept implantation ofimmunomodulatory porous regenerative scaffolds for in situ vascular engineering(IMPRESSIVE) as interposition grafts in sheep carotid arteries. These scaffolds are based on a new polyurethane (PU) material featuring a 40 µm precision porous structure optimized for angiogenesis. The modulus of the PU was adjusted to match that of natural arteries. The implantation study revealed rapid healing in IMPRESSIVE sVGs. In side-by-side comparison with standard polytetrafluoroethylene (PTFE) grafts, the luminal surfaces of PU grafts were almost completely covered with nucleated cells, while healing in PTFE grafts was limited to several millimeters within anastomotic regions. Endothelialization was observed in the middle regions of PU grafts and overall endothelialization increased significantly compared to PTFE grafts. Densities of mononuclear cells, foreign body giant cells (FBGCs), and endothelial cells within graft walls of PU grafts were also significantly higher than those in PTFE grafts, suggesting transmural cellular infiltration may play a key role in overall improved healing. High percentages of macrophages in pores of PU grafts show Type 1 (CCR7+) and Type 2 (mannose receptor, MR+) characteristics. We also discovered that FBGCs exist in a diverse spectrum of phenotypes. Dually activated FBGCs (CCR7+MR+, G1/2) dominate the population of FBGCs associated with pro-healing PU grafts. These observations suggest a complex, balanced pro-healing response from macrophages and FBGCs. The IMPRESSIVE approach may enable complete endothelialization in pro-healing sVGs and have wide applications in implantable devices and tissue engineering.
Characterizing substructure via mixture modeling in large-scale genetic summary statistics
Authors: Stoneman Hayley R , Price Adelle , Scribner Trout Nikole , Lamont Riley , Tifour Souha , Pozdeyev Nikita ,   Colorado Center for Personalized Medicine, Crooks Kristy , Lin Meng , Rafaels Nicholas , Gignoux Christopher R , Marker Katie M , Hendricks Audrey E
Published: January 2024

Genetic summary data are broadly accessible and highly useful including for risk prediction, causal inference, fine mapping, and incorporation of external controls. However, collapsing individual-level data into groups masks intra- and inter-sample heterogeneity, leading to confounding, reduced power, and bias. Ultimately, unaccounted substructure limits summary data usability, especially for understudied or admixed populations. Here, we presentSummix2, a comprehensive set of methods and software based on a computationally efficient mixture model to estimate and adjust for substructure in genetic summary data. In extensive simulations and application to public data,Summix2characterizes finer-scale population structure, identifies ascertainment bias, and identifies potential regions of selection due to local substructure deviation.Summix2increases the robust use of diverse publicly available summary data resulting in improved and more equitable research.
SCFFBXL5ubiquitin ligase regulates stability of von-Hippel Lindau protein and the HIF1α-dependent response to hypoxia
Authors: Mayank Adarsh K , Pandey Vijaya , Lien Kyle , Li Lu , Jami-Alahmadi Yasaman , Kassem Ahmad Mohammad , Wohlschlegel James A
Published: January 2024

The canonical response to changes in cellular oxygen levels consists of the ubiquitin-dependent degradation of hypoxia-inducible transcription factors (HIFs) in a prolyl hydroxylase (PHD) and von-Hippel Lindau-ElonginB-ElonginC (VHL-ElonginBC) E3 ubiquitin ligase complex-dependent manner. This regulated degradation event is oxygen-dependent and results in activation of a transcriptional program that mediates the cellular adaptation to changes in oxygen tension. Here, we show that a distinct Cullin-RING ligase complex, SKP1-CUL1-FBXL5 (SCFFBXL5), physically associates with VHL and promotes its ubiquitin-dependent degradation during hypoxia. The regulation of VHL protein stability by FBXL5 influences HIF1α expression levels and the transcriptional activation of downstream hypoxia-responsive target genes. This work identifies a novel mechanism for VHL regulation which contributes to the HIF1α-mediated cellular response to hypoxia and provides an additional layer of crosstalk between iron and oxygen homeostasis.
The Primate Cortical LFP Exhibits Multiple Spectral and Temporal Gradients and Widespread Task-Dependence During Visual Short-Term Memory
Authors: Hoffman Steven J. , Dotson Nicholas M. , Lima Vinicius , Gray Charles M.
Published: January 2024

Although cognitive functions are hypothesized to be mediated by synchronous neuronal interactions in multiple frequency bands among widely distributed cortical areas, we still lack a basic understanding of the distribution and task dependence of oscillatory activity across the cortical map. Here, we ask how the spectral and temporal properties of the local field potential (LFP) vary across the primate cerebral cortex, and how they are modulated during visual short-term memory. We measured the LFP from 55 cortical areas in two macaque monkeys while they performed a visual delayed match to sample task. Analysis of peak frequencies in the LFP power spectra reveals multiple discrete frequency bands between 3-80 Hz that differ between the two monkeys. The LFP power in each band, as well as the Sample Entropy, a measure of signal complexity, display distinct spatial gradients across the cortex, some of which correlate with reported spine counts in layer 3 pyramidal neurons. Cortical areas can be robustly decoded using a small number of spectral and temporal parameters, and significant task dependent increases and decreases in spectral power occur in all cortical areas. These findings reveal pronounced, widespread and spatially organized gradients in the spectral and temporal activity of cortical areas. Task-dependent changes in cortical activity are globally distributed, even for a simple cognitive task.